WO2018028634A1

WO2018028634A1 - Salts as hcv inhibitors

Info

Publication number: WO2018028634A1
Application number: PCT/CN2017/096814
Authority: WO
Inventors: Qingyun REN; Liang Chen; Yuefeng SHAN; Huichao LUO; Jinsheng Liang; Jianzhou HUANG; Jinfeng XIONG; Daojun ZHANG; Yingjun Zhang; Jiancun Zhang
Original assignee: Sunshine Lake Pharma Co., Ltd.
Priority date: 2016-08-11
Filing date: 2017-08-10
Publication date: 2018-02-15
Also published as: CN107722014A; TW201805289A; CN107722014B; HK1245775A1

Abstract

Salts of compound (I) and pharmaceutically compositions thereof, specially a base addition salt, an acid addition salt of compound (I) and a pharmaceutically composition thereof, future the use of the compound and the pharmaceutical composition in the manufacture of a medicament for preventing, managing, treating or lessening hepatitis C virus (HCV) infection.

Description

SALTS AS HCV INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of Chinese Patent Application Serial No. 201610655907.0, filed August 11, 2016, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention pertains to the medicine field, which relates to base addition salts, acid addition salts of compound (I) and pharmaceutical compositions thereof, further relates to use of the compound and the pharmaceutical composition in the manufacture of a medicament, specifically in the manufacture of a medicament for preventing, managing, treating or lessening hepatitis C virus (HCV) infection.

BACKGROUND ART

HCV is a major human pathogen, infecting an estimated 170 million persons worldwide roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma. Chronic HCV infection is thus a major worldwide cause of liver-related premature mortality.

HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5’ untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame (ORF) .

Considerable heterogeneity is found within nucleotide and encoded amino acid sequence throughout the HCV genome. At least seven major genotypes have been characterized, and more than 50 subtypes have been described. In HCV infected cells, viral RNA is translated into a polyprotein that is cleaved into ten individual proteins. At the amino terminus are structural proteins, follows E1 and E2. Additionally, there are six non-structural proteins, NS2, NS3, NS4A, NS4B, NS5A and NS5B, which play a function role in the HCV lifecycle (see, for example, Lindenbach et al., Nature, 2005, 436, 933-938) .

The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction； the second one is a serine protease within the N-terminal region of NS3 (also referred herein as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase that is involved in the replication of HCV.

Presently, the most effective HCV therapy employs a combination of alpha-interferon and ribavirin, leading to sustained efficacy in 40％of patients. Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy. However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. The treatment has side effects in many patients, so they do not durably respond to treatment. Thus, new and effective methods of treating HCV infection are urgently needed at present.

Patent application serial No. CN 2016100772777.8 described many HCV inhibitors, wherein compound (I) has a better inhibitory activity against HCV NS3/4A protein, but its exposure is unsatisfactory.

SUMMARY OF THE INVENTION

Various salts and solid forms of a drug active ingredient may have different properties. Various salts and solid forms can provide improved formulae due to their different properties. Therefore, in order to find a solid form having better druggability, the inventors obtained the pharmaceutically acceptable base addition salt, acid addition salt of compound (I) and pharmaceutical composition thereof unexpectedly through a lot of experiment researches, which have a better biological activity, and obviously improve the stability and pharmacokinetic properties of compound (I) , thereby have a better druggability.

The target of the present invention is to provide salts having HCV protein, such as NS3 protease inhibitory activity, which can be used for preparing a medicament for treating and lessening HCV infection and relative diseases.

The present invention relates to base addition salts, acid addition salts of compound (I) and pharmaceutical compositions thereof, further relates to use of the compound of the pharmaceutical composition in the manufacture of a medicament, specifically in the manufacture of a medicament for preventing, managing, treating or lessening hepatitis C virus (HCV) infection. The base addition salts or acid addition salts of compound (I) disclosed herein include hydrate or solvate forms.

In one aspect, the present invention provides a pharmaceutically acceptable base addition salt of compound (I) :

In some embodiments, the base addition salt provided herein is selected from at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminium salt, ferric salt, zinc salt, ammonium salt； or the salt is selected from at least one of salts formed by compound (I) and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethylaminoethanol , pyridine, methyl pyridine, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, piperidine, piperazine, morpholine, imidazole, lysine, arginine, L-arginine, histidine, N-methylglucosamine, dimethylglucosamine, ethylglucosamine, dicyclohexyl amine, 1, 6-hexanediamine, ethylenediamine, glucosamine, sarcosine, serinol, amino propanediol, 1-amino-2, 3, 4-butanetriol, L-lysine, ornithine.

In some embodiments, the base addition salt provided herein is N-methylglucosamine amorphism, wherein the N-methylglucosamine amorphism has an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments, the base addition salt provided herein is L-arginine amorphism, wherein the L-arginine amorphism has an X-ray powder diffraction pattern substantially as shown in figure 2.

In some embodiments, the base addition salt provided herein is L-lysine amorphism, wherein the L-lysine amorphism has an X-ray powder diffraction pattern substantially as shown in figure 3.

In some embodiments, the base addition salt provided herein is sodium salt amorphism, wherein the sodium salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 4.

In some embodiments, the base addition salt provided herein is calcium salt amorphism, wherein the calcium salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 5.

In some embodiments, the base addition salt provided herein is potassium salt amorphism, wherein the potassium salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 6.

In some embodiments, the base addition salt provided herein is lithium salt amorphism, wherein the lithium salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 7.

In some embodiments, the base addition salt provided herein is diethylamine salt amorphism, wherein the diethylamine salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 8.

In some embodiments, the base addition salt provided herein is tromethamine salt amorphism, wherein the tromethamine salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 9.

In some embodiments, the base addition salt provided herein is diethylaminoethanol salt amorphism, wherein the diethylaminoethanol salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 10.

In some embodiments, the base addition salt provided herein is piperazine salt amorphism, wherein the piperazine salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 11.

In some embodiments, the base addition salt provided herein is magnesium salt amorphism, wherein the magnesium salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 12.

In some embodiments, the base addition salt provided herein is dimethylethanolamine salt amorphism, wherein the dimethylethanolamine salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 13.

In some embodiments, the base addition salt provided herein is ethanediamine salt amorphism, wherein the ethanediamine salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 14.

In some embodiments, the base addition salt provided herein is triethanolamine salt amorphism, wherein the triethanolamine salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 15.

In some embodiments, the base addition salt provided herein is ethanol amine salt amorphism, wherein the ethanol amine salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 16.

In some embodiments, the base addition salt provided herein is imidazole salt amorphism, wherein the imidazole salt amorphism has an X-ray powder diffraction pattern substantially as shown in figure 17.

In other aspect, the present invention provides a pharmaceutically acceptable acid addition salt of compound (I) :

In some embodiments, the acid addition salts provided herein is an inorganic acid salt or organic acid salt, wherein the inorganic acid salt is selected from at least one of hydrochloride, sulfate, hydrosulfate, nitrate, hydrobromide, hydriodate, carbonate, hydrocarbonate, sulphite, hydrosulphite, pyrosulfate, monohydric phosphate, dihydric phosphate, perchlorate, persulfate, hemisulphate, bisulphate, thiocyanate, phosphate, pyrophosphate and metaphosphate； and organic acid salt is selected from at least one of formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, methanesulfate, esilate, propanesulfonate, 4-nitrobenzoate, benzene sulfonate, tosilate, 1, 2-ethanedisulphonate, β-naphthalenesulfonate, malate, propiolate, 2-butynate, 2-hydroxy-ethanesulfonate, vinyl acetate, tartrate, L-tartrate, fumarate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, mucate, gluceptate, mandelate, 1, 2-ethanedisulfonate, oxalate, trifluoroacetates, trifluoromethanesulfonate, adipate, suberate, sebacate, butyne-1, 4-dicarboxylate, hexyne-1, 6-dicarboxylate, glycollate, alginate, ascorbate, erythorbate, aspartate, L-aspartate, glutamate, L-glutamate, 2-phenoxybenzoate, 4'-hydroxybenzophenone-2-carboxylate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, camphorsulfonate, (-) -camphorsulfonate, toluate, dinitrobenzoate, sulfamate, galacturonate, cyclopentylpropionate, dodecylsulfate, acrylate, cypionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, enantate, caproate, pivalate, glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pectate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2, 2-dichloroacetate, acylation amino acid salt, alginate, 4-acetamidobenzenesulfonate, decanoate, cholate, caprylate, pelargonate, cyclamate, phthalate, cysteine hydrochloride, sorbate, glycine hydrochloride, 1, 5-naphthalenedisulfonate, xylene sulfonate, cystamine dihydrochloride, undecanoate, polyvinylsulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyvinylsulfate, 1-naphthalenesulfonate and valerate.

In some embodiments, the acid addition salt provided herein is citrate amorphism, wherein the citrate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 18.

In some embodiments, the acid addition salt provided herein is tosilate amorphism, wherein the tosilate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 19.

In some embodiments, the acid addition salt provided herein is benzene sulfonate amorphism, wherein the benzene sulfonate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 20.

In some embodiments, the acid addition salt provided herein is mesylate amorphism, wherein the mesylate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 21.

In some embodiments, the acid addition salt provided herein is sulfate amorphism, wherein the sulfate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 22.

In some embodiments, the acid addition salt provided herein is phosphate amorphism, wherein the phosphate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 23.

In some embodiments, the acid addition salt provided herein is nitrate amorphism, wherein the nitrate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 24.

In some embodiments, the acid addition salt provided herein is 1, 5-naphthalenedisulfonate amorphism, wherein the 1, 5-naphthalenedisulfonate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 25.

In some embodiments, the acid addition salt provided herein is 1, 2-ethanedisulphonate amorphism, wherein the 1, 2-ethanedisulphonate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 26.

In some embodiments, the acid addition salt provided herein is β-naphthalenesulfonate amorphism, wherein the β-naphthalenesulfonate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 27.

In some embodiments, the acid addition salt provided herein is cyclamate amorphism, wherein the cyclamate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 28.

In some embodiments, the acid addition salt provided herein is isethionate amorphism, wherein the isethionate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 29.

In some embodiments, the acid addition salt provided herein is maleate amorphism, wherein the maleate amorphism has an X-ray powder diffraction pattern substantially as shown in figure 30.

In some embodiments, the acid addition salt provided herein is hydrobromide amorphism, wherein the hydrobromide amorphism has an X-ray powder diffraction pattern substantially as shown in figure 31.

In some embodiments, the acid addition salt provided herein is hydrochloride amorphism, wherein the hydrochloride amorphism has an X-ray powder diffraction pattern substantially as shown in figure 32.

In other aspect, the present invention relates to a pharmaceutical composition, which comprises the acid addition salt of compound (I) or the base addition salt of compound (I) disclosed herein. Optionally the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.

In some embodiments, the pharmaceutical composition disclosed herein further comprises one or more other anti-HCV agents, wherein the other anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA for silencing or down-regulating positive-strand RNA genome of HCV, anti-sense RNA for silencing or down-regulating positive-strand RNA genome of HCV, imiquimod, an inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, bavituximab, CivacirTM, boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir, dasabuvir, beclabuvir, elbasvir, ombitasvir, neceprevir, tegobuvir, grazoprevir, sovaprevir, samatasvir, veruprevir, erlotinib, simeprevir, asunaprevir, vaniprevir, faldaprevir, VX-135, CIGB-230, furaprevir, pibrentasvir, glecaprevir, uprifosbuvir, radalbuvir, JHJ-56914845, vedroprevir, BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride, velpatasvir, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir (HCV-371) , VCH-916, lomibuvir, setrobuvir, MK-3281, ABT-072, filibuvir, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof； wherein the interferon is one of interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α and interferon γ or a combination thereof.

In some embodiments, the pharmaceutical composition disclosed herein further comprises at least one HCV inhibitor, wherein the HCV inhibitor inhibits HCV replication process and/or HCV viral protein function, and wherein the HCV replication process is selected from at least one of HCV entry, uncoating, translation, replication, assembly and egress process； and wherein the HCV viral protein is selected from at least one of metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A, NS5B, and an internal ribosome entry site (IRES) and inosine-5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.

In other aspect, the present invention relates to use of the acid addition salt or base addition salt of compound (I) or the pharmaceutical composition thereof in the manufacture of a medicament for inhibiting HCV replication process and/or HCV viral protein function, wherein the HCV replication process is selected from at least one of HCV entry, uncoating, translation, replication, assembly and egress process； and wherein the HCV viral protein is selected from at least one of metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A, NS5B, an internal ribosome entry site (IRES) and inosine-5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.

In other aspect, the present invention relates to use of the acid addition salt or base addition salt of compound (I) or the pharmaceutical composition thereof in the manufacture of a medicament for preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient.

In other aspect, the present invention relates to the base addition salt or acid addition salt ofcompound (I) or the pharmaceutical composition thereof for use in inhibiting HCV replication process and/or HCV viral protein function, wherein the HCV replication process is selected from at least one of HCV entry, uncoating, translation, replication, assembly and egress process； and wherein the HCV viral protein is selected from at least one of metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A, NS5B, and an internal ribosome entry site and inosine-5’ -monophosphate dehydrogenase required in HCV viral replication.

In other aspect, the present invention relates to the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition thereof for use in preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient.

In other aspect, the present invention relates to a method of inhibiting HCV replication process and/or HCV viral protein function, comprising administering the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition thereof to the patient, wherein the HCV replication process is selected from at least one of HCV entry, uncoating, translation, replication, assembly and egress process； and wherein the HCV viral protein is selected from at least one of metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A, NS5B, and an internal ribosome entry site and inosine-5’ -monophosphate dehydrogenase required in HCV viral replication.

In other aspect, the present invention relates to a method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient comprising administering the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition thereof to the patient.

DEFINITION OF TERMS

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described.

“Room temperature” of the invention refers to a temperature from about 10 ℃ to about 40 ℃. In some embodiments, “room temperature” refers to a temperature from about 20 ℃ to about 30 ℃； in other embodiments, “room temperature” refers to a temperature from about 25 ℃ to about 30 ℃； in still other embodiments “room temperature” refers to 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, etc.

“Pharmaceutically acceptable” of the invention means a substance is acceptable from the standpoint of toxicology for pharmaceutical applications and does not adversely interact with active ingredients.

“Pharmaceutically acceptable salts” refers to within the scope of sound medical judgment, the salt which is suitable for use in contact with human and lower animal tissue without excessive toxicity, irritation, allergic reactions, etc., and have quite a reasonable benefit/risk ratio. They are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmacol Sci, 66, 1997, 1-19, which is incorporated herein by reference.

The term “about” of the invention has its conventional meaning. In some embodiments when in relation to a numerical value, it may be interpreted to mean the numerical value ± 10％, or ± 5％, or ± 2％, or ± 1％, or ± 0.5％, or ± 0.1％. In other embodiments, the word “about” is left out so as to indicate that the precise value is meant.

The term “pharmaceutical acceptable acid addition salt” refers to an addition salt formed by compound (I) with an inorganic acid or an organic acid. Suitable inorganic acid salts include, but are not limited to: hydrochloride, sulfate, hydrosulfate, nitrate, hydrobromide, hydriodate, carbonate, hydrocarbonate, sulphite, hydrosulphite, pyrosulfate, monohydric phosphate, dihydric phosphate, perchlorate, persulfate, hemisulphate, bisulphate, thiocyanate, phosphate, pyrophosphate, metaphosphate； and suitable organic acid salt include, but are not limited to: formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, methanesulfate, esilate, propanesulfonate, citrate, 4-nitrobenzoate, benzene sulfonate, tosilate, malate, propiolate, 2-butynate, 2-hydroxyethanesulfonate, vinyl acetate, tartrate, L-tartrate, fumarate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, gluceptate, mandelate, 1, 2-ethanedisulfonate, oxalate, trifluoroacetates, trifluoromethanesulfonate, adipate, suberate, sebacate, butyne-1, 4-dicarboxylate, hexyne-1, 6-dicarboxylate, glycollate, alginate, ascorbate, erythorbate, aspartate, L-aspartate, glutamate, L-glutamate, 2-phenoxybenzoate, 4’-hydroxybenzophenone-2-carboxylate, acetoacetate, 2-hydroxy-ethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, camphorsulfonate, (-) -camphorsulfonate, toluate, dinitrobenzoate, sulfamate, galacturonate, cyclopentylpropionate, dodecylsulfate, acrylate, cypionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, enantate, caproate, pivalate, glucuronate, laurate, phthalate, phenylacetate, lauryl sulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pectate, phthalate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2, 2-dichloroacetate, acylation amino acid salt, alginate, 4-acetamidobenzenesulfonate, decanoate, cholate, caprylate, pelargonate, cyclamate, phthalate, cysteine hydrochloride, sorbate, glycine hydrochloride, naphthalenedisulfonate, xylene sulfonate, cystamine dihydrochloride, undecanoate, polyvinylsulfonate, sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, polyvinylsulfate, 1-naphthalenesulfonate and valerate.

The term “pharmaceutical acceptable base addition salt” refers to an addition salt formed by compound (I) with a base. Suitable base addition salts provided herein include, but are not limited to, lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminium salt, ferric salt, ferrous salt, a manganese salt, a manganous salt, a copper salt, a zinc salt and an ammonium salt； or a salt formed by compound (I) and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethylaminoethanol, pyridine, methyl pyridine, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethyl-ammonium, tetraethylammonium, triethanolamine, piperidine, piperazine, morpholine, imidazole, lysine, arginine, L-arginine, histidine, N-methylglucosamine, dimethylglucosamine, ethylglucosamine, dicyclohexyl amine , 1, 6-hexanediamine, ethylenediamine, glucosamine, sarcosine, serinol, amino propanediol , 1-amino-2, 3, 4-butanetriol, L-lysine and ornithine.

“Amorphism” or “amorphous form” refers to substance forming by particle (such as molecule, atom, ion) arranged in no periodic in three-dimensional space, which is characterized by a diffused X-ray powder diffraction pattern with no sharp peaks. Amorphism is a special physical form of solid substance, the ordered structural characteristics in a part of amorphous substance imply there are innumerable links between amorphous substance and crystal substance. Amorphous substance can be obtained through many methods as known in the art. These methods include, but are not limited to, rapid freezing method, anti-solvent flocculence method, ball-milling method, spray drying method, freeze-drying method, wet granulating method and solid dispersion technique, and the like.

The term “solvent, ” means a substance, typically a liquid, that is capable of completely or partially dissolving another substance, typically a solid. Solvents for the practice of the invention include, but are not limited to, water, acetic acid, ethyl ether, isopropyl ether, petroleum ether, isopropyl acetate, propyl acetate, methyl tert-butyl ether, n-heptane, a mixture of ethanol and water at a volume ratio from 10: 90 to 90: 10, a mixture of methanol and dichloromethane at a volume ratio from 2: 1 to 1: 2, acetone, acetonitrile, benzene, chloroform, tetrachloromethane, dichloromethane, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, n-butanol, tert-butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, hexane, isopropanol, methanol, methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, n-propanol, 2-acetone, pyridine, tetrahydrofuran, methyl ethyl ketone, toluene, xylene, mixtures thereof etc.

The term “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein, or a salt amorphism of the compound disclosed herein adsorbed with a solvent molecule on the surface. Some non-limiting examples of the solvent that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , dichloromethane, ethyl acetate, acetic acid, ethanolamine, a mixture of methanol and dichloromethane at a volume ratio from 2: 1 to 1: 2. The term “hydrate” refers to an association of water molecules and a compound disclosed herein, or a salt amorphism of the compound disclosed herein adsorbed with a water molecule on the surface.

Amorphism can be identified through multiple technological means, such as X-ray powder diffraction (XRPD) , infrared spectroscopy (IR) , melting point method, differential scanning calorimetry (DSC) , thermogravimetry analysis (TGA) , nuclear magnetic resonance method, Raman spectroscopy, X-ray single crystal diffraction, solution calorimetry, scanning electron microscope (SEM) , quantitative analysis, solubility, dissolution velocity, etc..

In the present invention, the base addition salt or acid addition salt may contain solvent, some common solvents include water, ethanol, methanol, isopropanol, propyl acetate, tetrahydrofuran, acetone, isopropyl ether, ethyl ether, isopropyl acetate, n-heptane, ethyl acetate, a mixture of methanol and dichloromethane at a volume ratio from 2: 1 to 1: 2, etc. As long as the base addition salt or acid addition salt containing a certain amount of water or other solvent has any feature of the base addition salt or acid addition salt disclosed herein, all should be considered included in the scope of the present invention.

As used herein, the value of 2θ described in an X-ray powder diffraction pattern is recorded in degree (°) .

The term “substantially the same as shown in a figure” refers to an X-ray powder diffraction (XRPD) pattern has at least 50％, at least 60％, at least 70％, at least 80％, at least 90％, at least 95％, or at least 99％of the peaks shown in the figure.

As used herein, when referring to a spectrum and/or to data presented in a figure, the term “peak” refers to a feature that one skilled in the art would recognize and would not be attributed to background noise.

As used herein, the term “relative intensity” refers to the intensity of a peak with respect to the intensity of the strongest peak in the X-ray powder diffraction (XRPD) pattern which is regarded as 100％.

As used in the context of the present invention, regardless of whether the word “about” is used, which means within 10％, suitably within 5％and particularly within 1 ％of a given value or range. Alternatively, the term “about” means within an acceptable standard error of the mean for those of ordinary skill in the art. Whenever a number having a value N is disclosed, any number having the value within N+/-1％, N+/-2％, N+/-3％, N+/-5％, N+/-7％, N+/-8％or N+/-10％is specifically disclosed, wherein “+/-” refers to plus or minus.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (conformational isomerism) ) forms of the structure； for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, or geometric mixtures of the present compounds are within the scope disclosed herein.

Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Isotopically enriched forms of the compounds have the structure given herein, except one or more atoms are replaced by the atom having the selective atomic weight or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H (deuterium, D) , ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵I, respectively.

In another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, for example those into which radioactive isotopes, such as ³H, ¹⁴C and ¹⁸F, or those into which non-radioactive isotopes, such as ²H and ¹³C are present. Such isotopically enriched compounds are useful in metabolic studies (with ¹⁴C) , reaction kinetic studies (with, for example ²H or ³H) , detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F-enriched compound may be particularly desirable for PET or SPECT studies. Isotopically-enriched compound (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Further, substitution with heavier isotopes, particularly deuterium (i.e., ²H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of compound (I) . The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5％deuterium incorporation at each designated deuterium atom) , at least 4000 (60％deuterium incorporation) , at least 4500 (67.5％deuterium incorporation) , at least 5000 (75％deuterium incorporation) , at least 5500 (82.5％deuterium incorporation) , at least 6000 (90％deuterium incorporation) , at least 6333.3 (95％deuterium incorporation) , at least 6466.7 (97％deuterium incorporation) , at least 6600 (99％deuterium incorporation) , or at least 6633.3 (99.5％deuterium incorporation) . Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, DMSO-d₆.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York； and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley&Sons, Inc., New York, 1994. The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center (s) . The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The term “racemic mixture” or “racemate” refers to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The base addition salt or acid addition salt or the pharmaceutical composition of the invention are suitable for the method of treating HCV infection or diseases relative to HCV infection in a mammal (especially a human) , the method comprises administering a salt amorphism of compound (I) to the mammal in need of treatment.

PHARMACEUTICAL COMPOSITIONS OF SALTS OF THE COMPOUND OF THE INVENTION, PREPARATIONS AND ADMINISTRATION

As described above, the pharmaceutical composition disclosed herein comprises any one of the base addition salt or acid addition salt of compound (I) , further comprises a pharmaceutically acceptable adjuvant, such as a carrier, a diluent, a filler, a binder, a corrigent or an excipient, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. As described in following references: In Remington: Troy et al., Remington: The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams &Wilkins, Philadelphia, and Swarbrick et al., Encyclopedia of Pharmaceutical Technology, eds. 1988-1999, Marcel Dekker, New York, both of which are herein incorporated by reference in their entireties, discloses various adjuvants used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional adjuvant incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other components of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.

Some non-limiting examples of materials which can serve as pharmaceutically acceptable adjuvants include ion exchangers； aluminium； aluminum stearate； lecithin； serum proteins such as human serum albumin； buffer substances such as phosphates； glycine； sorbic acid； potassium sorbate； partial glyceride mixtures of saturated vegetable fatty acids； water； salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride and zinc salts； colloidal silica； magnesium trisilicate； polyvinyl pyrrolidone； polyacrylates； waxes； polyethylene-polyoxypropylene-block polymers； wool fat； sugars such as lactose, glucose and sucrose； starches such as corn starch and potato starch； cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate； powdered tragacanth； malt； gelatin； talc； excipients such as cocoa butter and suppository waxes； oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil； glycols such as propylene glycol and polyethylene glycol； esters such as ethyl oleate and ethyl laurate； agar； buffering agents such as magnesium hydroxide and aluminum hydroxide； alginic acid； pyrogen-free water； isotonic saline； Ringer’s solution； ethyl alcohol； and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

The pharmaceutical composition disclosed herein further comprises anti-HCV agents. The anti-HCV agent may be any other known anti-HCV agents except the compound described herein. For example, the anti-HCV agent may be interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA for silencing or down-regulating positive-strand RNA genome of HCV, anti-sense RNA for silencing or down-regulating positive-strand RNA genome of HCV, imiquimod, an inosine 5’-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, bavituximab, Civacir^TM, boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127) , dasabuvir (ABT-333) , beclabuvir (BMS-791325) , elbasvir (MK-8742) , ombitasvir (ABT-267) , neceprevir (ACH-2684) , tegobuvir (GS-9190) , grazoprevir (MK-5172) , sovaprevir (ACH-1625) , samatasvir (IDX-719) , veruprevir (ABT-450) , erlotinib, simeprevir (TMC-435) , asunaprevir (BMS-650032) , vaniprevir (MK-7009) , faldaprevir (BI-2013335) , VX-135, CIGB-230, furaprevir (TG-2349) , pibrentasvir (ABT-530) , glecaprevir (ABT-493) , uprifosbuvir (IDX-21437) , radalbuvir (GS-9669) , JHJ-56914845, vedroprevir (GS-9451) , BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride (PPI-668) , velpatasvir (GS-5816) , MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420) , VBY-376, TMC-649128, mericitabine (R-7128) , INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir (HCV-371) , VCH-916, lomibuvir (VCH-222) , setrobuvir (ANA-598) , MK-3281, ABT-072, filibuvir (PF-00868554) , deleobuvir (BI-207127) , A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof； wherein the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, interferon γ or a combination thereof. Wherein the interfering RNA for silencing or down-regulating positive-strand RNA genome of HCV is RNA specifically targeted positive-strand RNA genome of HCV, which degrades positive-strand RNA genome of HCV (i.e. messenger RNA) by interference of RNA, for regulating expression of positive-strand RNA genome of HCV after transcriptional level； the anti-sense RNA for silencing or down-regulating positive-strand RNA genome of HCV is RNA specifically combining to positive-strand RNA of HCV by specific complementary pairing, on the one hand which prevents ribosomes to bind with positive strand RNA of HCV by steric hindrance effect formed by combining with positive-strand RNA genome of HCV, on the other hand which combines with positive-strand RNA of HCV to activate endogenous RNA enzyme or ribozyme, and then degrades positive-strand RNA of HCV to realize silencing or down-regulation of positive-strand RNA genome of HCV. The pharmaceutical composition further comprises at least one HCV inhibitor, wherein the HCV inhibitor inhibits HCV replication process and/or HCV viral protein function, and wherein the HCV replication process comprises HCV entry, uncoating, translation, replication, assembly and egress； and wherein the HCV viral protein is selected from metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, and an internal ribosome entry site (IRES) and inosine-5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication.

When it is possible that, for use in therapy, therapeutically effective amounts of the salt of the compound (I) of the invention, as well as pharmaceutically acceptable base addition salts or acid addition salts thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. The invention further provides pharmaceutical compositions, which comprise therapeutically effective amounts of the salt of the compound of the invention, especially the base addition salt or acid addition salt of compound (I) , and one or more pharmaceutically acceptable carrier, diluent or excipient. The term “therapeutically effective amount, ” as used herein, refers to the total amount of each active component that is sufficient to show a meaningful patient benefit (e.g., a reduction in viral load) . When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. The salt of the compound of the invention, specificially the base addition salts or acid addition salts of compound (I) disclosed herein described above. The carrier (s) , diluent (s) , or excipient (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation including admixing the salt of the compound of the invention, specificailly the base addition salt or acid addition salt of compound (I) with one or more pharmaceutically acceptable carriers, diluents, or excipients. The term “pharmaceutically acceptable, ” as used herein, refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram (mg/kg) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Treatment may be initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmful or deleterious side effects.

When the pharmaceutical compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent, both the compound and the additional agent are usually present at dosage levels of between about 10 to 150％, and more preferably between about 10 to 80％of the dosage normally administered in a monotherapy regimen. Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual) , rectal, nasal, topical (including buccal, sublingual, or transdermal) , vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier (s) or excipient (s) . Oral administration or administration by injection is preferred.

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets； powders or granules； solution or suspensions in aqueous or non-aqueous liquids； edible foams or whips； or oil-in-water liquid emulsions or water-in-oil emulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweetener, natural and synthetic resin such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitable comminuted, with a diluents or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solution of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulation, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating of embedding particulate material in polymers, wax, or the like.

The base addition salt or acid addition salt of compound (I) or pharmaceutical composition thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.

The base addition salt or acid addition salt of compound (I) or pharmaceutical composition thereof may also be delivered by the use of monoclonal antibodies as individual carrier to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine, substituted by palmitoyl radicals. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, poly (ε-caprolactone) , polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmacol. Res., 1986, 3 (6) , 318.

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patch.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, insufflators or other device suitable for delivery aerosol sprays.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient； and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

It should be understood that in addition to ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

USE OF THE SALTS AND PHARMACEUTICAL COMPOSITIONS

Provided herein is use of the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition in the manufacture of a medicament for inhibiting HCV replication process and/or HCV viral protein function, and the HCV replication process comprises HCV entry, uncoating, translation, replication, assembly and egress； and wherein the HCV viral protein is selected from metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, and an internal ribosome entry site (IRES) and inosine-5’ -monophosphate dehydrogenase (IMPDH) required in HCV viral replication. Any compound or pharmaceutical composition of the invention can be used for treating HCV infection or a HCV disorder, especially which has a good inhibitory effect on NS3/4A protein.

The treating method that comprises administering with the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition of the invention, further comprising administering with additional anti-HCV agent to a patient, therefore, the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition of the invention can be use for combination therapy with the additional anti-HCV agent, wherein the anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA for silencing or down-regulating positive-strand RNA genome of HCV, anti-sense RNA for silencing or down-regulating positive-strand RNA genome of HCV, imiquimod, an inosine 5'-monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, bavituximab, CivacirTM, boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir (BI-207127) , dasabuvir (ABT-333) , beclabuvir (BMS-791325) , elbasvir (MK-8742) , ombitasvir (ABT-267) , neceprevir (ACH-2684) , tegobuvir (GS-9190) , grazoprevir (MK-5172) , sovaprevir (ACH-1625) , samatasvir (IDX-719) , setrobuvir, veruprevir (ABT-450) , erlotinib, simeprevir (TMC-435) , asunaprevir (BMS-650032) , vaniprevir (MK-7009) , faldaprevir (BI-2013335) , VX-135, CIGB-230, furaprevir (TG-2349) , pibrentasvir (ABT-530) , glecaprevir (ABT-493) , uprifosbuvir (IDX-21437) , radalbuvir (GS-9669) , JHJ-56914845, vedroprevir (GS-9451) , BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride (PPI-668) , velpatasvir (GS-5816) , MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin (EP-013420) , VBY-376, TMC-649128, mericitabine (R-7128) , sofosbuvir (PSI-7977) , INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir (HCV-371) , VCH-916, lomibuvir (VCH-222) , setrobuvir (ANA-598) , MK-3281, ABT-072, filibuvir (PF-00868554) , deleobuvir (BI-207127) , A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof； wherein the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, interferon γ or a combination thereof.

The treatment method that includes administering the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition of the invention, further includes administering to the patient an additional anti-HCV agent, wherein the additional anti-HCV drug is administered together with the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition as a single dosage form or separately from the base addition salt or acid addition salt of compound (I) or the pharmaceutical composition as part of a multiple dosage form. The additional anti-HCV agent may be administered at the same time as the base addition salt or acid addition salt of compound (I) disclosed herein or at a different time. In the latter case, administration may be staggered by, for example, 6 hours, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 1 month, or 2 months.

An “effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition is an amount that is effective in treating or lessening the severity of one or more of the aforementioned disorders. The base addition salt or acid addition salt of compound (I) and compositions, according to the method disclosed herein, may be administered using any amount and any route of administration which is effective for treating or lessening the severity of the disorder or disease. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. A compound or composition can also be administered with one or more other therapeutic agents as discussed above.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows that the X-ray powder diffraction pattern of N-methylglucosamine salt amorphism of compound (I) ；

Figure 2 shows that the X-ray powder diffraction pattern of L-arginine salt amorphism of compound (I) ；

Figure 3 shows that the X-ray powder diffraction pattern of L-lysine salt amorphism of compound (I) ；

Figure 4 shows that the X-ray powder diffraction pattern of sodium salt amorphism of compound (I) ；

Figure 5 shows that the X-ray powder diffraction pattern of calcium salt amorphism of compound (I) ；

Figure 6 shows that the X-ray powder diffraction pattern of potassium salt amorphism of compound (I) ；

Figure 7 shows that the X-ray powder diffraction pattern of lithium salt amorphism of compound (I) ；

Figure 8 shows that the X-ray powder diffraction pattern of diethylamine salt amorphism of compound (I) ；

Figure 9 shows that the X-ray powder diffraction pattern of tromethamine amorphism of compound (I) ；

Figure 10 shows that the X-ray powder diffraction pattern of diethylaminoethanol salt amorphism of compound (I) ；

Figure 11 shows that the X-ray powder diffraction pattern of piperazidine salt amorphism of compound (I) ；

Figure 12 shows that the X-ray powder diffraction pattern of magnesium salt amorphism of compound (I) ；

Figure 13 shows that the X-ray powder diffraction pattern of dimethylethanolamine salt amorphism of compound (I) ；

Figure 14 shows that the X-ray powder diffraction pattern of ethanediamine salt amorphism of compound (I) ；

Figure 15 shows that the X-ray powder diffraction pattern of triethanolamine salt amorphism of compound (I) ；

Figure 16 shows that the X-ray powder diffraction pattern of ethanol amine salt amorphism of compound (I) ；

Figure 17 shows that the X-ray powder diffraction pattern of imidazole salt amorphism of compound (I) ；

Figure 18 shows that the X-ray powder diffraction pattern of citrate amorphism of compound (I) ；

Figure 19 shows that the X-ray powder diffraction pattern of tosilate amorphism of compound (I) ；

Figure 20 shows that the X-ray powder diffraction pattern of benzene sulfonate amorphism of compound (I) ；

Figure 21 shows that the X-ray powder diffraction pattern of mesylate amorphism of compound (I) ；

Figure 22 shows that the X-ray powder diffraction pattern of sulfate amorphism of compound (I) ；

Figure 23 shows that the X-ray powder diffraction pattern of phosphate amorphism of compound (I) ；

Figure 24 shows that the X-ray powder diffraction pattern of nitrate amorphism of compound (I) ；

Figure 25 shows that the X-ray powder diffraction pattern of 1, 5-naphthalenedisulfonate amorphism of compound (I) ；

Figure 26 shows that the X-ray powder diffraction pattern of 1, 2-ethanedisulphonate amorphism of compound (I) ；

Figure 27 shows that the X-ray powder diffraction pattern of β-naphthalenesulfonate amorphism of compound (I) ；

Figure 28 shows that the X-ray powder diffraction pattern of cyclamate amorphism of compound (I) ；

Figure 29 shows that the X-ray powder diffraction pattern of isethionate amorphism of compound (I) ；

Figure 30 shows that the X-ray powder diffraction pattern of maleate amorphism of compound (I) ；

Figure 31 shows that the X-ray powder diffraction pattern of hydrobromide amorphism of compound (I) ；

Figure 32 shows that the X-ray powder diffraction pattern of hydrochloride amorphism of compound (I) .

GENERAL SYNTHETIC PROCEDURES

In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius (℃) . Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory.

NMR spectra were recorded by a Bruker Avance 400 MHz spectrometer or Bruker Avance III HD 600 spectrometer, using CDCl3, -DMSO-d6, CD3OD or acetone-d6 (reported in ppm) as solvent, and using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When peak multiplicities are reported, the following abbreviations are used: s (singlet) , d (doublet) , t (triplet) , m (multiplet) , br (broadened) , dd (doublet of doublets) , ddd (doublet of doublet of doublets) , dt (doublet of triplets) , ddt (doublet of doublet of triplets) , td (triplet of doublets) , br. s (broadened singlet) . Coupling constants J, when given, were reported in Hertz (Hz) .

The X ray powder diffraction analysis method disclosed herein is: X-ray powder diffraction diagram was recorded on an Empyrean diffraction, using Cu-Kα radiation (45 KV, 40 mA) . A thin layer was prepared from powder sample on the single-crystal silicon sample holder, and which was put on a rotary sample stage and, analyzed in the range from 3° to 40°with a 0.0168° step size. Data were collected by Data Collector software, and processed by HighScore Plus software, read by Data Viewer software.

The test data of element content of the invention were detected through Agilent 7700X series ICP-MS equipped with G31XXB vacuum system, HMI high matrix introduction sampler and new dual-mode detector are applied in analysis, inductively coupled plasma (ICP) source is applied in ICP-MS Mass spectrometer.

The solubility disclosed herein was measured by Aglient 1200 high performance liquid chromatograph VWD detector. The chromatographic column model is Waters Xbridge-C18 (4.6 × 150 mm, 5 μm) . Detection wavelength is 250 nm, flow rate is 1.0 mL/min, the column temperature is 35 ℃, mobile phase is acetonitrile-water (V/V ＝ 40/60) .

Low-resolution mass spectral (MS) data were also determined on an Agilent 6320 series LC-MS spectrometer equipped with G1312A binary pumps, a G1316A TCC (Temperature Control of Column, maintained at 30 ℃) , a G1329A autosampler and a G1315B DAD detector were used in the analysis. An ESI source was used on the LC-MS spectrometer.

Low-resolution mass spectral (MS) data were also determined on an Agilent 6120 series LC-MS spectrometer equipped with G1311A quaternary pumps, a G1316A TCC (Temperature Control of Column, maintained at 30 ℃) , a G1329A autosampler and a G1315D DAD detector were used in the analysis. An ESI source was used on the LC-MS spectrometer.

Both LC-MS spectrometers were equipped with an Agilent Zorbax SB-C18, 2.1 x 30 mm, 5 μm column. Injection volume was decided by the sample concentration. The flow rate was 0.6 mL/min. The HPLC peaks were recorded by UV-Vis wavelength at 210 nm and 254 nm. The mobile phase was 0.1％formic acid in acetonitrile (phase A) and 0.1％formic acid in ultrapure water (phase B) . The gradient elution conditions is showed in Table 1:

Table 1: The gradient condition of the mobile phase in Low-resolution mass spectrum analysis

Time (min)	A (CH₃CN, 0.1％HCOOH)	B (H₂O, 0.1％HCOOH)
0-3	5-100	95-0
3-6	100	0
6-6.1	100-5	0-95
6.1-8	5	95

Purities of compounds were assessed by Agilent 1100 Series high performance liquid chromatography (HPLC) with UV detection at 210 nm and 254 nm (Zorbax SB-C18, 2.1 × 30 mm, 4 micorn, 10 min, 0.6 mL/min flow rate, 5 to 95 ％ (0.1 ％formic acid in CH₃CN) in (0.1 ％formic acid in H₂O) . Column was operated at 40 ℃.

Preparative separation of compounds were assessed by Agilent 1260 Series high performance liquid chromatography (HPLC) with UV detection at 278 nm, Calesil ODS-120 (4.6× 250 mm, 120 A, 10 u) column, 1.0 mL/min flow rate, mobile phase is 10 mM ZnSO₄+ 20 mM L-valine buffer : methanol (V: V ＝ 50: 50) . Column was operated at 30 ℃.

The following abbreviations are used throughout the specification:

Ac acetyl

Ac₂O acetic anhydride

BOC, Boc tert-butoxycarbonyl

(Boc) ₂O Di-tert-butyl dicarbonate

CHCl₃ chloroform

CDC1₃ chloroform-d

DCM, CH₂Cl₂ dichloromethane

CDI 1, 1'-carbonyldiimidazole

DBU 1, 8-diazabicyclo [5.4.0] undec-7-ene

DMF N, N-dimethylformamide

DMAP 4-dimethylaminopyridine

DMSO dimethylsulfoxide

DIPEA N, N-diisopropylethylamine

DIAD diisopropyl azodicarboxylate

DME 2-methoxyethyl ether

EDC, EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EtOAc ethyl acetate

EA ethyl acetate

Et₃N, TEA triethylamine

EtOH ethyl alcohol

MeCN, CH3CN acetonitrile

THF tetrahydrofuran

HCl·EA, HCl/EA a hydrogen chloride solution in ethyl acetate

HOAt, HOAT N-hydroxy-7-azabenzotriazole

HOAc acetic acid

g gram

mg milligram

ml, mL milliliter

IPA isopropanol

Pd(PPh₃) ₄ tetrakis (triphenylphosphine) platinum

RT rt room temperature

rf reflux

Rt retention time

EXAMPLES

The following examples disclosed herein are presented to further describe the invention. However, these examples should not be used to limit the scope of the invention.

Synthesis method of amorphism of compound (I)

Step 1) Preparation of compound 1-2

A mixture of compound 1-1 (50 g, 216 mmol) , triphenylphosphine (68 g, 259 mmol) and dichloromethane (375 mL) in a flask was cooled to -10 ℃ under N2, and then DIAD (52.5 g， 260 mmol) was added dropwsie. After the addition, the mixture was stirred at -10 ℃ for 3 hours. After the reaction was complete, methanesulfonic acid (62.5 g, 650 mmol) was added, and the mixture was stirred at 40 ℃ for 2 hours. After the reaction was complete, the mixture was cooled to rt and filtered. The filter cake was washed with a little of dichloromethane once and dried at 40 ℃ in vacuo for 4 hours to give compound 1-2 (40 g, 88.4％) as a white solid.

Step 2) Preparation of compound 1-3

To a mixture of compound 1-2 (10 g, 47.8 mmol) , compound 7 (10 g, 36.8 mmol) , ethyl cyanoglyoxylate-2-oxime (1.3 g, 9.1 mmol) , DIPEA (9.0 mL, 54 mmol) and dichloromethane (250 mL) in a flask was added EDCI (0.85 g, 4.4 mmol) under N₂. The mixture was stirred at rt for 3 hours. After the reaction was complete, to the mixture was added water (250 mL) . The organic layer was washed with aqueous citric acid solution (10％, 250 mL) , saturated aqueous sodium bicarbonate solution (250 mL) and saturated aqueous sodium chloride solution (250mL) in turn, and dried over anhydrous Na₂SO₄ and concentrated in vacuo to give compound 1-3 (12.7 g, 94.1％) as brownish red oil

Step 3) Preparation of compound 1-5

A 250 mL of single neck flask was charged with compound 1-3 (13.37 g, 36.49 mmol) , toluene (13 mL) and water (130 mL) , and then followed by the addition of compound 1-4 (11.66 g, 37.20 mmol) and sodium 2-ethylhexanoate (10.00 g, 54.85 mmol) . The mixture was stirred at rt overnight. After the reaction was complete, the mixture was extracted with EtOA (150 mL×2) . The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (150 mL) , hydrochloric acid (1 mol/L, 150 mL) and saturated aqueous sodium chloride solution , and dried over anhydrous Na2SO4 and concentrated in vacuo to give compound 1-5 (18.52 g, 100％) as brownish red oil.

Step 4) Preparation of compound 1-7

A 250 mL of single neck flask were charged with compound 1-5 (18.5 g, 36.4 mmol) , compound 1-6 (10.48 g, 47.3 mmol) and toluene (100 mL) . The mixture was cooled to -10 ℃, and a solution of potassium tert-butoxide (6.12 g， 54.6 mmol) in anhydrous tetrahydrofuran (20 mL) was added slowly, the reaction temperature was maintained not higher than -5 ℃. After the addition, the mixture was further stirred at -5 ℃ for 3 hours. After the reaction was complete, to the mixture was added hydrochloric acid (100 mL, 1 mol/L) . The resulting mixture was stirred at rt for 30 min. The aqueous phase was extracted with toluene (100 mL) . The organic phases were combined. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (100 mL) , hydrochloric acid (150 mL, 1 mol/L) once, and then washed with saturated aqueous sodium chloride solution at last, and dried over anhydrous Na₂SO₄ and concentrated in vacuo to give compound 1-7 (24.0 g, 97.6％) as brownish red oil.

Step 5) Preparation of compound 1-9

A 250 mL of single neck flask were charged with compound 1-7 (24 g, 35.4 mmol) , compound 1-8 (10 g, 31.8 mmol) , cesium carbonate (15 g, 46 mmol) and 1-methyl-2-pyrrolidinone (70 mL) . The mixture was stirred at 50 ℃ overnight. After the reaction was complete, the mixture was participated between water (100 mL) and tert-butyl methyl ether (70 mL) . The aqueous phase was extracted with tert-butyl methyl ether (70 mL) . The combined organic phases were washed with saturated aqueous sodium bicarbonate (70 mL) and saturated aqueous sodium chloride in turn, and dried over anhydrous Na₂SO₄ and concentrated in vacuo to give brownish red oil. The oil was suspended in isopropanol (210 mL) and the mixture was warmed and stirred until dissolved completely. And then the mixture was cooled to rt and compound 1-9 (20.0 g, 80％) precipitated out as a white solid.

Step 6) Preparation of compound 1-10

A mixture of compound 1-9 (20 g, 24.8 mmol) and toluene (1400 mL) was refluxed at 110 ℃ for 1 hour. To the mixture was added a solution of Zhan catalyst (0.08 g, 0.1 mmol) in toluene (200 mL) under N₂ over 3 hours. After the addition, the mixture was refluxed for 2 hours. After the reaction was complete, the mixture was concentrated in vacuo to give brownish grey oil, the oil was suspended in methyl tert-butyl ether (80 mL) and the mixture was refluxed and stirred until dissolved completely. And then the mixture was cooled to rt and compound 1-10 (15.0 g, 80％) precipitated out as a white solid.

Step 7) Preparation of compound 1-11

A mixture of compound 1-10 (10 g, 12.89 mmol) , lithium hydroxide monohydrate (1.1 g, 26 mmol) , methanol (40 mL) , tetrahydrofuran (40 mL) and water (20 mL) in a 250 mL of single neck flask was stirred at rt overnight. After the reaction was complete, the mixture was concentrated in vacuo, and to the residue was added hydrochloric acid (50 mL, 1 mol/mL) and EtOAc (50 mL) . The aqueous phase was extracted with EtOAc (50 mL) . The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous Na₂SO₄, and concentrated in vacuo to give compound 1-11 (9.15 g, 93.2％) as a white solid.

Step 8) Preparation of compound 1-13

A mixture of compound 1-11 (2 g, 2.625 mmol) , CDI (0.87 g, 5.3 mmol) and dichloromethane (20 mL) was stirred at rt for 3 hours, and DBU (0.82 g, 5.3 mmol) and compound 1-12 (0.72 g, 5.3 mmol) were added. The resulting mixture was stirred at rt overnight. After the reaction was complete, to the mixture was added hydrochloric acid (40 mL, 1 mol/mL) , the mixture was partitioned. The aqueous phase was extracted with dichloromethane (10 mL) . The combined organic phases were washed with saturated aqueous sodium chloride (50 mL) and dried over anhydrous Na₂SO₄, and concentrated in vacuo to give compound 1-13 (2.2 g, 94.42％) as a light yellow solid.

MS (ESI, pos. ion) m/z: 880.8 [M+1] ⁺；

¹H NMR (600 MHz, CDCl₃) : δ 10.31 (s, 1H) , 8.03 (d, J ＝ 7.5 Hz, 1H) , 7.93 (s, 1H) , 7.84 –7.79 (m, 2H) , 7.54 (s, 1H) , 7.06 –7.01 (m, 2H) , 5.70 (dd, J ＝ 17.9, 8.7 Hz, 1H) , 5.52 (s, 1H) , 5.03 –4.98 (m, 1H) , 4.76 –4.69 (m, 2H) , 4.65 –4.60 (m, 1H) , 4.13 –4.09 (m, 1H) , 3.89 (s, 3H) , 3.73 (s, 3H) , 3.26 –3.19 (m, 2H) , 2.75 (dd, J ＝ 13.8, 7.4 Hz, 1H) , 2.65 (s, 3H) , 2.31 (d, J ＝ 8.6 Hz, 1H) , 2.07 –2.04 (m, 1H) , 1.85 (dd, J ＝ 15.5, 9.2 Hz, 2H) , 1.78 (dd, J ＝ 10.5, 5.1 Hz, 1H) , 1.66 –1.62 (m, 1H) , 1.50 (d, J ＝ 7.3 Hz, 4H) , 1.40 (d, J ＝ 6.9 Hz, 7H) , 1.26 (d, J ＝ 4.2 Hz, 3H) , 1.20 (s, 3H) , 0.86 –0.77 (m, 3H) ppm.

Step 9) Preparation of compound (I)

A solution of compound 1-13 (0.2 g, 0.2 mmol) in isopropanol (2 mL) was cooled to 0 ℃, and a solution of HCl in isopropanol (mass fraction: 40％, 5 mL) was added. The mixture was stirred until no more gas evolution. The mixture was filtered to afford a white solid, the solid was washed with EtOAc (5 mL) . A round-bottom flask was charged with the white solid, compound 1-14 (0.1 g, 0.7 mmol) , EDCI (0.2 g, 1.5 mmol) and HOAT (0.15 g, 1.1 mmol) , and then dichloromethane (10 mL) was added under N₂. The mixture was cooled to 0 ℃, and DIPEA (0.5 mL, 3 mmol) was added slowly. The mixture was stirred at 30 ℃ for 6 hours. After the reaction was complete, the mixture was quenched with water (10 mL) . The resulting mixture was extracted with dichloromethane (10 mL) twice. The combined organic layers were washed with saturated aqueous NaCl (10 mL) and dried over anhydrous Na₂SO₄, and then concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with PE : EtOAc (V: V) ＝ 2: 1 to give compound (I) (0.150 g, 70％) as a white solid.

MS (ESI, pos. ion) m/z: 874.3 [M+1] ⁺；

¹H NMR (600 MHz, CDCl₃) : δ 10.30 (s, 1H) , 8.40 (s, 1H) , 7.95 (d, J ＝ 7.4 Hz, 1H) , 7.87 (d, J ＝ 9.1 Hz, 1H) , 7.81 (s, 1H) , 7.55 (s, 1H) , 7.04 (d, J ＝ 9.2 Hz, 2H) , 6.57 (s, 1H) , 5.63 (dd, J ＝ 17.8, 8.6 Hz, 1H) , 5.51 (d, J ＝ 27.3 Hz, 1H) , 4.92 (t, J ＝ 9.4 Hz, 1H) , 4.76 (t, J ＝ 7.3 Hz, 1H) , 4.70 (t, J ＝ 7.8 Hz, 1H) , 4.58 (d, J ＝ 11.4 Hz, 1H) , 4.16 –4.10 (m, 1H) , 3.88 (s, 3H) , 3.26 –3.20 (m, 2H) , 2.75 (dd, J ＝ 13.6, 7.7 Hz, 1H) , 2.65 (d, J ＝ 18.3 Hz, 4H) , 2.54 –2.48 (m, 1H) , 2.38 (s, 1H) , 2.26 (dd, J ＝ 17.2, 8.5 Hz, 1H) , 2.05 (dd, J ＝ 21.8, 10.4 Hz, 1H) , 1.89 –1.83 (m, 1H) , 1.79 –1.69 (m, 2H) , 1.43 (d, J ＝ 5.5 Hz, 2H) , 1.39 (d, J ＝ 6.9 Hz, 7H) , 1.28 –1.23 (m, 3H) , 1.19 (s, 3H) , 0.96 –0.66 (m, 3H) ppm.

The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 33.

Example 1 Preparation and identification of N-methylglucosamine salt amorphism of compound (I)

1. Preparation of N-methylglucosamine salt amorphism of compound (I)

To methanol (20.0 mL) were added compound (I) (0.437 g, 0.491 mmol) and N-methylglucosamine (0.106 g, 0.543 mmol) , the solid was dissolved slowly, the reaction mixture was reacted for 7 hours at rt. After the reaction was complete, the solvent was removed in vacuo, the solid was dried in vacuo at rt to get N-methylglucosamine salt amorphism of compound (I) as a white solid powder (0.523 g, 0.489 mmol, 99.61％) .

2. Identification of N-methylglucosamine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (s, 1H) , 8.45 (d, J ＝ 5.6 Hz, 1H) , 8.01 (d, J ＝ 9.1 Hz, 2H) , 7.50 (d, J ＝ 31.5 Hz, 2H) , 7.35 (d, J ＝ 9.3 Hz, 1H) , 6.82 (s, 1H) , 5.62 (s, 1H) , 5.51 (t, J ＝ 9.7 Hz, 1H) , 5.34 (d, J ＝ 6.8 Hz, 1H) , 4.77 (s, 1H) , 4.57 –4.37 (m, 3H) , 4.21 (d, J ＝ 9.7 Hz, 1H) , 3.93 (s, 3H) , 3.81 (d, J ＝ 4.1 Hz, 1H) , 3.66 (d, J ＝ 4.3 Hz, 1H) , 3.60 (dd, J ＝ 10.7, 3.2 Hz, 2H) , 3.52 –3.47 (m, 2H) , 3.45 –3.41 (m, 4H) , 3.21 –3.12 (m, 2H) , 2.88 (dt, J ＝ 11.9, 8.7 Hz, 3H) , 2.58 (s, 3H) , 2.53 (d, J ＝ 9.4 Hz, 2H) , 2.27 –1.87 (m, 5H) , 1.74 (s, 1H) , 1.51 –1.10 (m, 20H) , 0.48 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 1.

Example 2 Preparation and identification of L-arginine salt amorphism of compound (I)

1. Preparation of L-arginine salt amorphism of compound (I)

To methanol (20.0 mL) were added compound (I) (0.437 g, 0.50 mmol) and L-arginine (0.092 g, 0.531 mmol) , the solid was dissolved slowly, the reaction mixture was reacted overnight at rt. After the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at rt to get L-arginine salt amorphism of compound (I) as a white solid powder (0.52 g, 0.497 mmol, 99.31％) .

2. Identification of L-arginine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (d, J ＝ 1.2 Hz, 1H) , 8.43 (s, 1H) , 8.16 –7.95 (m, 2H) , 7.49 (d, J ＝ 30.5 Hz, 5H) , 7.35 (d, J ＝ 9.3 Hz, 1H) , 6.82 (d, J ＝ 1.2 Hz, 1H) , 5.56 (dd, J ＝ 24.0, 13.9 Hz, 2H) , 5.33 (dd, J ＝ 16.5, 9.5 Hz, 1H) , 4.78 (s, 1H) , 4.53 (t, J ＝ 7.8 Hz, 1H) , 4.42 (d, J ＝ 11.6 Hz, 1H) , 4.20 (d, J ＝ 8.2 Hz, 1H) , 3.92 (s, 3H) , 3.30 (d, J ＝ 6.0 Hz, 3H) , 3.21 –3.02 (m, 4H) , 2.57 (s, 5H) , 2.22 –1.84 (m, 4H) , 1.79 –1.06 (m, 24H) , 0.46 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 2.

Example 3 Preparation and identification of L-lysine salt amorphism of compound (I)

1. Preparation of L-lysine salt amorphism of compound (I)

To methanol (20.0 mL) were added compound (I) (0.449 g, 0.514 mmol) and L-lysine (0.083 g, 0.568 mmol) , the solid was dissolved slowly, the reaction mixture was reacted for 4.5 hours at rt, after the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at rt to get L-lysine salt amorphism of compound (I) as a white solid powder (0.524 g, 0.514 mmol, 99.98％) .

2. Identification of L-lysine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.08 (s, 1H) , 8.41 (s, 1H) , 8.10 –7.88 (m, 2H) , 7.50 (d, J ＝ 29.0 Hz, 2H) , 7.36 (d, J ＝ 9.3 Hz, 1H) , 6.83 (s, 1H) , 5.56 (dd, J ＝ 24.7, 14.4 Hz, 2H) , 5.31 (dd, J ＝ 16.9, 9.3 Hz, 1H) , 4.79 (s, 1H) , 4.52 (t, J ＝ 7.8 Hz, 1H) , 4.42 (d, J ＝ 11.5 Hz, 1H) , 4.22 (d, J ＝ 9.6 Hz, 1H) , 3.93 (s, 3H) , 3.16 (dd, J ＝ 14.4, 7.2 Hz, 3H) , 2.73 (t, J ＝ 7.1 Hz, 2H) , 2.56 (d, J ＝ 16.2 Hz, 5H) , 2.17 –1.84 (m, 5H) , 1.81 –1.54 (m, 4H) , 1.53 –1.03 (m, 24H) , 0.45 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 3.

Example 4 Preparation and identification of sodium salt amorphism of compound (I)

1. Preparation of sodium salt amorphism of compound (I)

Compound (I) (501 mg, 0.573 mmol) was dispersed in methanol (15 mL) , and to the solution was added sodium hydroxide (23 mg, 0.564 mmol) aqueous (1.4 mL) solution, the reaction mixture was reacted for 5.5 hours at rt, after the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at 60 ℃ overnight to get sodium salt amorphism of compound (I) as a light yellow solid (0.502 g, 0.56 mmol, 97.7％) .

2. Identification of sodium salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.08 (s, 1H) , 8.41 (d, J ＝ 6.5 Hz, 1H) , 8.05 –7.91 (m, 2H) , 7.53 (s, 1H) , 7.46 (s, 1H) , 7.35 (d, J ＝ 9.3 Hz, 1H) , 6.84 (d, J ＝ 1.3 Hz, 1H) , 5.66 –5.54 (m, 2H) , 5.32 (dd, J ＝ 16.7, 9.5 Hz, 1H) , 4.80 (s, 1H) , 4.53 (t, J ＝ 7.8 Hz, 1H) , 4.41 (d, J ＝ 11.6 Hz, 1H) , 4.21 (d, J ＝ 8.4 Hz, 1H) , 3.93 (s, 3H) , 3.16 (dt, J ＝ 13.7, 6.8 Hz, 1H) , 2.56 (d, J ＝ 13.8 Hz, 4H) , 2.12 (s, 2H) , 1.93 (dt, J ＝ 17.9, 7.9 Hz, 2H) , 1.75 (t, J ＝ 12.2 Hz, 1H) , 1.51 –1.10 (m, 20H) , 0.47 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 4.

3) Detecting and analyzing the content of metallic element, the mole ratio of compound (I) and sodium ion is 1: 1.

Example 5 Preparation and identification of calcium salt amorphism of compound (I)

1. Preparation of calcium salt amorphism of compound (I)

To methanol (40 mL) was added sodium salt of compound (I) (2000 mg, 2.232 mmol) , the mixture was heated to reflux, the solid was dissolved, and to the mixture was added a calcium chloride (123.9 mg, 1.116 mmol) aqueous (60 mL) solution dropwise within 1 hour. The resulting mixture was stirred for 3 hours under holding temperature, and stopping heat, the mixture was cooled to rt naturally, and stirred overnight, and then water (60 mL) was added, solid precipitated, the mixture was continued to stir for 2 hours and filtered by suction, the filter cake was washed with a mixture of methanol and water (V/V＝1/1) , and dried in vacuo at 70 ℃overnight to get calcium salt amorphism of compound (I) as a light yellow powder (1.10 g, 0.62 mmol, 55％) .

2. Identification of calcium salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.08 (s, 1H) , 8.42 (d, J ＝ 6.1 Hz, 1H) , 8.08 (s, 1H) , 8.02 (d, J ＝ 9.2 Hz, 1H) , 7.53 (s, 1H) , 7.46 (s, 1H) , 7.36 (d, J ＝ 9.3 Hz, 1H) , 6.83 (s, 1H) , 5.67 –5.50 (m, 2H) , 5.35 (d, J ＝ 7.3 Hz, 1H) , 4.77 (s, 1H) , 4.53 (t, J ＝ 7.8 Hz, 1H) , 4.42 (d, J ＝ 11.3 Hz, 1H) , 4.19 (d, J ＝ 8.0 Hz, 1H) , 3.93 (s, 3H) , 3.16 (dt, J ＝ 13.6, 6.7 Hz, 1H) , 2.64 –2.52 (m, 5H) , 2.24 –1.66 (m, 5H) , 1.53 –1.07 (m, 19H) , 0.51 (s, 2H) .

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 5.

Example 6 Preparation and identification of potassium salt amorphism of compound (I)

1. Preparation of potassium salt amorphism of compound (I)

Method one: Compound (I) (498 mg, 0.557 mmol) was dissolved in a mixture of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) ＝ 1/1) , the solution was stirred at rt, and to the solution was added a solution of potassium isooctanoate (102 mg, 0.557 mmol) in a mixture of methanol and dichloromethane (5 mL, methanol/dichloromethane (V/V) ＝ 1/1) dropwise slowly. The resulting mixture was stirred at rt overnight. After the reaction was complete, the solvent was removed in vacuo, the residue was dried at rt in vacuo for 4 hours to get potassium salt amorphism of compound (I) (0.506 g, 0.555 mmol, 99.6％) as a light yellow solid.

Method two: Compound (I) (502 mg, 0.574 mmol) was dispersed in methanol (15 mL) , and to the solution was added potassium hydroxide (32 mg, 0.570mmol) aqueous (0.58 mL) solution, the system became clear slowly, the resulting mixture was stirred at rt overnight. After the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at 60 ℃ overnight to get potassium salt amorphism of compound (I) as a light yellow solid (0.50g, 0.55 mmol, 95.0％) .

2. Identification of potassium salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (s, 1H) , 8.47 (s, 1H) , 8.01 (d, J ＝ 9.1 Hz, 2H) , 7.53 (s, 1H) , 7.45 (s, 1H) , 7.34 (d, J ＝ 9.2 Hz, 1H) , 6.83 (s, 1H) , 5.78 –5.24 (m, 3H) , 4.76 (s, 1H) , 4.64 –4.33 (m, 2H) , 4.16 (dd, J ＝ 24.8, 7.1 Hz, 1H) , 3.92 (s, 3H) , 3.23 –3.10 (m, 1H) , 2.57 (s, 4H) , 2.19 (s, 1H) , 1.97 (s, 3H) , 1.72 (s, 1H) , 1.55 –1.00 (m, 20H) , 0.51 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 6.

Example 7 Preparation and identification of lithium salt amorphism of compound (I)

1. Preparation of lithium salt amorphism of compound (I)

Compound (I) (500 mg, 0.572 mmol) was dispersed in methanol (10 mL) , and to the solution was added lithium hydroxide (24 mg, 0.572 mmol) aqueous (1 mL) solution with stirring at rt, after the addition, the resulting mixture was stirred at rt overnight. After the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at 60 ℃ for 4 hours to get lithium salt amorphism of compound (I) as a light yellow solid (0.49g, 0.557 mmol, 97.3％) .

2. Identification of lithium salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (s, 1H) , 8.43 (s, 1H) , 8.05 (s, 1H) , 8.02 (d, J ＝9.2 Hz, 1H) , 7.54 (s, 1H) , 7.46 (s, 1H) , 7.36 (d, J ＝ 9.3 Hz, 1H) , 6.83 (s, 1H) , 5.58 (d, J ＝ 29.7 Hz, 2H) , 5.36 (s, 1H) , 4.77 (s, 1H) , 4.53 (t, J ＝ 7.8 Hz, 1H) , 4.42 (d, J ＝ 10.3 Hz, 1H) , 4.19 (d, J ＝ 9.0 Hz, 1H) , 3.93 (s, 3H) , 3.24 –3.11 (m, 1H) , 2.58 (s, 5H) , 2.18 (s, 1H) , 2.07 (s, 1H) , 1.96 (s, 2H) , 1.73 (s, 1H) , 1.52 –1.32 (m, 16H) , 1.24 –1.08 (m, 3H) , 0.50 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 7.

Example 8 Preparation and identification of diethylamine salt amorphism of compound (I)

1. Preparation of diethylamine salt amorphism of compound (I)

To a 50 mL of single neck flask was added compound (I) (499 mg, 0.561 mmol) and methanol (10 mL) , the mixture was stirred at rt, and then to the solution was added a diethylamine (41.8 mg, 0.561 mmol) /methanol (1 mL) solution, after the addition, the resulting mixture was stirred at rt overnight. After the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at rt to get diethylamine salt amorphism of compound (I) as a light yellow solid powder (0.522 g, 0.551 mmol, 98.3％) .

2. Identification of diethylamine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (d, J ＝ 1.2 Hz, 1H) , 8.56 (s, 1H) , 8.27 (s, 1H) , 8.03 (d, J ＝ 9.2 Hz, 1H) , 7.54 (s, 1H) , 7.46 (s, 1H) , 7.35 (d, J ＝ 9.3 Hz, 1H) , 6.82 (d, J ＝ 1.2 Hz, 1H) , 5.64 (s, 1H) , 5.41 (s, 2H) , 4.72 (s, 1H) , 4.50 (dd, J ＝ 14.8, 7.1 Hz, 2H) , 4.17 (d, J ＝ 8.4 Hz, 1H) , 3.93 (s, 3H) , 3.17 (dt, J ＝ 13.6, 6.8 Hz, 2H) , 2.90 (q, J ＝ 7.2 Hz, 4H) , 2.58 (s, 5H) , 2.29 (s, 1H) , 1.99 (d, J ＝ 11.0 Hz, 3H) , 1.69 (s, 1H) , 1.53 –1.09 (m, 25H) , 0.57 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 8.

Example 9 Preparation and identification of tromethamine salt amorphism of compound (I)

1. Preparation of tromethamine salt amorphism of compound (I)

To a 50 mL of single neck flask was added compound (I) (500 mg, 0.562 mmol) and a mixture of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) ＝ 1/1) , the mixture was stirred at rt and dissolved, and then to the solution was added a tromethamine (69.5 mg, 0.562 mmol) /methanol (2 mL) solution. After the addition, the resulting mixture was stirred at rt for 60 min. After the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at rt to get tromethamine salt amorphism of compound (I) as a light yellow solid (0.551g, 0.554 mmol, 99.3％) .

2. Identification of tromethamine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (d, J ＝ 0.8 Hz, 1H) , 8.48 (d, J ＝ 6.2 Hz, 1H) , 8.24 –7.95 (m, 2H) , 7.54 (s, 1H) , 7.46 (s, 1H) , 7.35 (d, J ＝ 9.3 Hz, 1H) , 6.82 (d, J ＝ 1.1 Hz, 1H) , 5.62 (s, 1H) , 5.48 (t, J ＝ 9.9 Hz, 1H) , 5.35 (dd, J ＝ 16.7, 9.4 Hz, 1H) , 5.02 (s, 3H) , 4.76 (s, 1H) , 4.59 –4.39 (m, 2H) , 4.21 (d, J ＝ 8.2 Hz, 1H) , 3.92 (s, 3H) , 3.45 (s, 6H) , 3.17 (dt, J ＝ 16.1, 6.9 Hz, 2H) , 2.57 (s, 5H) , 2.19 (s, 1H) , 1.99 (dt, J ＝ 17.6, 8.4 Hz, 3H) , 1.73 (s, 1H) , 1.57 –1.08 (m, 20H) , 0.50 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 9.

Example 10 Preparation and identification of diethylaminoethanol salt amorphism of compound (I)

1. Preparation of diethylaminoethanol salt amorphism of compound (I)

To a 25 mL of single neck flask was added compound (I) (501mg, 0.563 mmol) and a mixture of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) ＝ 1/1) , the mixture was stirred at rt and dissolved, and then to the solution was added a diethylaminoethanol (67.2 mg, 0.563 mmol) /ethanol (0.95 mL) solution, after the addition, the resulting mixture was stirred at rt for 2.5 hours. After the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at rt to get diethylaminoethanol salt amorphism of compound (I) as a light yellow solid (0.552 g, 0.557 mmol, 98.9％) .

2. Identification of diethylaminoethanol salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (s, 1H) , 8.65 (s, 1H) , 8.44 (s, 1H) , 8.04 (d, J ＝9.1 Hz, 1H) , 7.55 (s, 1H) , 7.46 (s, 1H) , 7.34 (d, J ＝ 9.3 Hz, 1H) , 6.80 (s, 1H) , 5.65 (s, 1H) , 5.38 (d, J ＝ 53.9 Hz, 2H) , 4.67 (s, 1H) , 4.58 –4.44 (m, 2H) , 4.14 (d, J ＝ 9.1 Hz, 1H) , 3.93 (s, 3H) , 3.58 (t, J ＝ 5.7 Hz, 2H) , 3.17 (dt, J ＝ 13.6, 6.8 Hz, 2H) , 2.83 (s, 6H) , 2.69 –2.55 (m, 4H) , 2.38 (s, 1H) , 2.13 (s, 1H) , 2.04 –1.85 (m, 2H) , 1.65 (s, 1H) , 1.55 –1.18 (m, 20H) , 1.08 (t, J ＝ 7.1 Hz, 6H) , 0.66 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 10.

Example 11 Preparation and identification of piperazidine salt amorphism of compound (I)

1. Preparation of piperazidine salt amorphism of compound (I)

To methanol (10.0 mL) were added compound (I) (0.212 g, 0.243 mmol) and piperazidine (0.029 g, 0.337 mmol) , the solid was dissolved slowly, the reaction mixture was reacted overnight at rt, after the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at rt to get piperazidine salt amorphism of compound (I) as a white solid powder (0.23 g, 0.24 mmol, 98.75％) .

2. Identification of piperazidine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.08 (s, 1H) , 8.43 (d, J ＝ 5.7 Hz, 1H) , 8.13 –7.97 (m, 2H) , 7.53 (s, 1H) , 7.46 (s, 1H) , 7.36 (d, J ＝ 9.3 Hz, 1H) , 6.83 (s, 1H) , 5.58 (dd, J ＝ 21.4, 11.3 Hz, 2H) , 5.34 (dd, J ＝ 16.5, 9.7 Hz, 1H) , 4.78 (s, 1H) , 4.53 (t, J ＝ 7.8 Hz, 1H) , 4.42 (d, J ＝ 11.6 Hz, 1H) , 4.19 (d, J ＝ 8.1 Hz, 1H) , 3.93 (s, 3H) , 3.16 (dt, J ＝ 13.7, 6.9 Hz, 1H) , 2.80 (s, 8H) , 2.61 –2.52 (m, 5H) , 2.01 (ddd, J ＝ 30.3, 27.2, 21.7 Hz, 4H) , 1.72 (d, J ＝ 12.0 Hz, 1H) , 1.51 –1.05 (m, 21H) , 0.47 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 11.

Example 12 Preparation and identification of magnesium salt amorphism of compound (I)

1. Preparation of magnesium salt amorphism of compound (I)

Compound (I) (500 mg, 0.562 mmol) was dispersed in methanol (15 mL) , and to the solution was added a magnesium hydroxide (16.4 mg, 0.281 mmol) aqueous (1 mL) solution, the resulting mixture was stirred at rt overnight. After the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at 60 ℃ overnight to get magnesium salt amorphism of compound (I) as a light yellow solid (0.497 g, 0.279 mmol, 99.1％) .

2. Identification of magnesium salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (s, 1H) , 8.44 (s, 1H) , 8.02 (d, J ＝ 8.8 Hz, 1H) , 7.54 (s, 1H) , 7.46 (s, 1H) , 7.36 (d, J ＝ 9.2 Hz, 1H) , 6.82 (s, 1H) , 5.63 (s, 2H) , 5.39 (s, 1H) , 4.74 (s, 1H) , 4.59 –4.35 (m, 2H) , 4.30 –4.02 (m, 1H) , 3.93 (s, 3H) , 3.25 –3.08 (m, 1H) , 2.58 (s, 5H) , 1.97 (t, J ＝ 101.9 Hz, 5H) , 1.61 –0.81 (m, 20H) , 0.57 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 12.

Example 13 Preparation and identification of dimethylethanolamine salt amorphism of compound (I)

1. Preparation of dimethylethanolamine salt amorphism of compound (I)

Compound (I) (500 mg, 0.562 mmol) was added to a mixture of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) ＝1/1) , the mixture was stirred at rt and dissolved, and then to the solution was added a dimethylethanolamine (51.1mg, 0.562 mmol) /methanol (1 mL) solution, the resulting mixture was stirred at rt for 3 hours. After the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at rt to get dimethylethanolamine salt amorphism of compound (I) as a light yellow solid powder (0.526g, 0.546 mmol, 97.2％) .

2. Identification of dimethylethanolamine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (s, 1H) , 8.68 (d, J ＝ 5.4 Hz, 1H) , 8.49 (s, 1H) , 8.04 (d, J ＝ 9.2 Hz, 1H) , 7.56 (s, 1H) , 7.47 (s, 1H) , 7.34 (d, J ＝ 9.3 Hz, 1H) , 6.80 (s, 1H) , 5.66 (s, 1H) , 5.48 (dd, J ＝ 17.5, 8.5 Hz, 1H) , 5.30 (t, J ＝ 9.3 Hz, 1H) , 4.79 (s, 1H) , 4.66 (s, 1H) , 4.55 (d, J ＝ 11.5 Hz, 1H) , 4.49 (t, J ＝ 8.1 Hz, 1H) , 4.13 (d, J ＝ 8.2 Hz, 1H) , 3.93 (s, 3H) , 3.57 (t, J ＝ 5.8 Hz, 2H) , 3.17 (dt, J ＝ 14.3, 6.9 Hz, 2H) , 2.69 (t, J ＝ 5.8 Hz, 2H) , 2.63 (dd, J ＝ 13.7, 7.5 Hz, 1H) , 2.58 (s, 3H) , 2.44 (s, 6H) , 2.15 (d, J ＝ 8.2 Hz, 1H) , 1.97 (dd, J ＝ 24.2, 13.6 Hz, 2H) , 1.69 –1.18 (m, 21H) , 0.68 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 13.

Example 14 Preparation and identification of ethanediamine salt amorphism of compound (I)

1. Preparation of ethanediamine salt amorphism of compound (I)

Compound (I) (503 mg, 0.565 mmol) was dissolved in a mixture of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) ＝ 1/1) , the solution was stirred at rt, and to the solution was added an ethanediamine (34.7 mg, 0.565 mmol) /methanol (1 mL) solution dropwise slowly. The resulting mixture was stirred at rt for 3 hours. After the reaction was complete, the solvent was removed in vacuo, the residue was dried at rt in vacuo to get ethanediamine salt amorphism of compound (I) (0.523 g, 0.560 mmol, 99.1％) as a light yellow solid powder.

2. Identification of ethanediamine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.08 (s, 1H) , 8.43 (s, 1H) , 8.01 (d, J ＝ 9.2 Hz, 2H) , 7.54 (s, 1H) , 7.46 (s, 1H) , 7.36 (d, J ＝ 9.3 Hz, 1H) , 6.83 (s, 1H) , 5.62 (s, 1H) , 5.55 (t, J ＝ 10.0 Hz, 1H) , 5.33 (dd, J ＝ 16.5, 9.6 Hz, 1H) , 4.78 (d, J ＝ 6.0 Hz, 1H) , 4.52 (t, J ＝ 7.8 Hz, 1H) , 4.43 (d, J ＝ 11.6 Hz, 1H) , 4.20 (d, J ＝ 7.8 Hz, 1H) , 3.93 (s, 3H) , 3.74 (s, 4H) , 3.17 (dq, J ＝ 13.7, 6.9 Hz, 2H) , 2.74 (s, 4H) , 2.58 (s, 3H) , 2.23 –2.01 (m, 2H) , 2.02 –1.86 (m, 2H) , 1.74 (s, 1H) , 1.51 –1.05 (m, 20H) , 0.47 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 14.

Example 15 Preparation and identification of triethanolamine salt amorphism of compound (I)

1. Preparation of triethanolamine salt amorphism of compound (I)

Compound (I) (505 mg, 0.565 mmol) was dissolved in a mixture of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) ＝ 1/2) , the solution was stirred at rt, and to the solution was added a triethanolamine (85.9 mg, 0.565 mmol) /methanol (1.5 mL) solution dropwise slowly. The resulting mixture was stirred at rt for 3.5 hours. After the reaction was complete, the solvent was removed in vacuo, the residue was dried at rt in vacuo to get triethanolamine salt amorphism of compound (I) (0.565 g, 0.552 mmol, 97.8％) as a light yellow solid powder.

2. Identification of triethanolamine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (d, J ＝ 1.4 Hz, 1H) , 8.83 (s, 2H) , 8.32 –8.29 (m, 1H) , 8.05 (d, J ＝ 9.2 Hz, 1H) , 7.57 (s, 1H) , 7.47 (s, 1H) , 7.34 (d, J ＝ 9.3 Hz, 1H) , 6.79 (d, J ＝1.2 Hz, 1H) , 5.62 (d, J ＝ 48.4 Hz, 2H) , 5.16 (s, 1H) , 5.16 (s, 2H) , 4.50 (dd, J ＝ 35.3, 27.2 Hz, 6H) , 4.10 (s, 1H) , 3.94 (s, 3H) , 3.48 (s, 6H) , 3.17 (dt, J ＝ 13.6, 6.8 Hz, 2H) , 2.63 (d, J ＝ 36.4 Hz, 10H) , 2.33 (s, 1H) , 2.14 –1.72 (m, 2H) , 1.65 –1.14 (m, 21H) , 0.80 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 15.

Example 16 Preparation and identification of ethanolamine salt amorphism of compound (I)

1. Preparation of ethanolamine salt amorphism of compound (I)

Compound (I) (503 mg, 0.565 mmol) was dissolved in a mixture of methanol and dichloromethane (15 mL, methanol/dichloromethane (V/V) ＝1/2) , the solution was stirred at rt, and to the solution was added an ethanolamine (35.2 mg, 0.565 mmol) /methanol (1 mL) solution dropwise. The resulting mixture was stirred at rt for 3.5 hours. After the reaction was complete, the solvent was removed in vacuo, the residue was dried at rt in vacuo to get triethanolamine salt amorphism of compound (I) (0.52 g, 0.560 mmol, 98.0％) as a light yellow solid powder.

2. Identification of ethanolamine salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.08 (d, J ＝ 0.9 Hz, 1H) , 8.43 (d, J ＝ 5.3 Hz, 1H) , 8.01 (d, J ＝ 8.9 Hz, 2H) , 7.53 (s, 1H) , 7.46 (s, 1H) , 7.35 (d, J ＝ 9.3 Hz, 1H) , 6.83 (d, J ＝ 1.0 Hz, 1H) , 5.56 (dd, J ＝ 24.7, 14.5 Hz, 2H) , 5.33 (dd, J ＝ 16.6, 9.8 Hz, 1H) , 4.78 (s, 1H) , 4.60 –4.36 (m, 2H) , 4.21 (d, J ＝ 8.1 Hz, 1H) , 3.93 (s, 3H) , 3.56 –3.53 (m, 2H) , 3.17 (dq, J ＝ 13.8, 6.9 Hz, 2H) , 2.82 (t, J ＝ 5.4 Hz, 2H) , 2.56 (d, J ＝ 13.0 Hz, 5H) , 2.22 –1.86 (m, 4H) , 1.74 (t, J ＝ 12.1 Hz, 1H) , 1.55 –1.04 (m, 20H) , 0.47 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 16.

Example 17 Preparation and identification of imidazole salt amorphism of compound (I)

1. Preparation of imidazole salt amorphism of compound (I)

To acetone (10 mL) were added compound (I) (0.38 g, 0.435 mmol) and imidazole (0.03 g, 0.441 mmol) , the solid was dissolved, the reaction mixture was reacted for 7.5 hours at rt, after the reaction was complete, the solvent was removed in vacuo, the residue was dried in vacuo at rt to get imidazole salt amorphism of compound (I) as a white solid powder (0.39 g, 0.414 mmol, 95.21％) .

2. Identification of imidazole salt amorphism of compound (I)

1) ¹H NMR (600 MHz, DMSO-d₆) δ 9.07 (s, 1H) , 8.98 –8.73 (m, 2H) , 8.06 (d, J ＝ 9.2 Hz, 1H) , 7.71 (s, 1H) , 7.57 (s, 1H) , 7.47 (s, 1H) , 7.34 (d, J ＝ 9.3 Hz, 1H) , 7.05 (s, 2H) , 6.78 (d, J ＝ 1.3 Hz, 1H) , 5.76 –5.50 (m, 2H) , 5.12 (t, J ＝ 9.5 Hz, 1H) , 4.65 (d, J ＝ 11.5 Hz, 1H) , 4.55 (s, 1H) , 4.49 –4.43 (m, 1H) , 4.06 (d, J ＝ 8.8 Hz, 1H) , 3.94 (s, 3H) , 3.17 (dt, J ＝ 13.6, 6.8 Hz, 1H) , 2.75 –2.54 (m, 5H) , 2.49 –2.30 (m, 2H) , 2.00 (d, J ＝ 10.9 Hz, 1H) , 1.77 (d, J ＝ 5.1 Hz, 1H) , 1.64 –1.13 (m, 20H) , 0.91 –0.75 (m, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 17.

Example 18 Preparation and identification of citrate amorphism of compound (I)

1. Preparation of citrate amorphism of compound (I)

Compound (I) (204 mg, 0.228 mmol) was dispersed in methanol (4.0 mL) , and to the solution was added a citric acid (46.1 mg, 0.239 mmol) /methanol (1.0 mL) solution, and then dichloromethane (4.0 mL) was added. The resulting solution was stirred at rt for 4 hours, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get citrate amorphism of compound (I) (206 mg, 0.201mmol, 88.2％) as a light yellow solid.

2. Identification of citrate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.16 (s, 1H) , 8.44 (d, J ＝ 1.5 Hz, 1H) , 8.03 (d, J ＝ 7.1 Hz, 1H) , 7.91 (d, J ＝ 9.1 Hz, 1H) , 7.64 (d, J ＝ 7.6 Hz, 1H) , 7.57 (s, 1H) , 7.27 (s, 1H) , 7.11 (d, J ＝9.2 Hz, 1H) , 7.06 (s, 1H) , 6.62 (d, J ＝ 1.5 Hz, 1H) , 5.73 (dd, J ＝ 18.1, 8.6 Hz, 1H) , 5.09 –4.93 (m, 1H) , 4.80 (t, J ＝ 7.2 Hz, 1H) , 4.70 (t, J ＝ 7.9 Hz, 1H) , 4.58 (d, J ＝ 11.5 Hz, 1H) , 4.16 (dd, J ＝ 11.4, 3.6 Hz, 1H) , 3.93 (s, 3H) , 3.24 (dt, J ＝ 13.8, 6.9 Hz, 1H) , 2.97 (s, 2H) , 2.89 (s, 2H) , 2.79 –2.73 (m, 2H) , 2.70 (s, 3H) , 2.58 (s, 1H) , 2.31 (dd, J ＝ 17.4, 8.8 Hz, 1H) , 2.06 (dd, J ＝ 23.1, 11.4 Hz, 1H) , 1.83 (ddd, J ＝ 27.3, 19.0, 9.2 Hz, 8H) , 1.53 –1.48 (m, 6H) , 1.41 (d, J ＝ 6.9 Hz, 6H) , 1.30 (d, J ＝ 14.1 Hz, 2H) , 0.87 –0.79 (m, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 18.

Example 19 Preparation and identification of tosilate amorphism of compound (I)

1. Preparation of tosilate amorphism of compound (I)

Compound (I) (623 mg, 0.705 mmol) was dispersed in a mixture of methanol (12.0 mL) and dichloromethane (7.0 mL) , to the solution was added a p-toluene sulfonic acid (137 mg, 0.706mmol) /methanol (4.5 mL) solution. The resulting solution was stirred at rt for 4 hours, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get tosilate amorphism of compound (I) (720 mg, 0.69 mmol, 97.9％) as a yellow solid.

2. Identification of tosilate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H) , 8.38 (s, 1H) , 8.20 (s, 1H) , 8.07 (d, J ＝ 9.1 Hz, 1H) , 7.95 (s, 1H) , 7.78 (d, J ＝ 7.7 Hz, 2H) , 7.48 (d, J ＝ 7.1 Hz, 1H) , 7.36 (s, 1H) , 7.18 (dd, J ＝ 19.0, 8.5 Hz, 3H) , 6.48 (s, 1H) , 5.80 (s, 1H) , 5.65 (dd, J ＝ 18.1, 8.5 Hz, 1H) , 5.05 (t, J ＝9.5 Hz, 1H) , 4.87 (t, J ＝ 7.8 Hz, 1H) , 4.65 (s, 1H) , 4.37 (d, J ＝ 11.7 Hz, 1H) , 4.12 (d, J ＝ 8.9 Hz, 1H) , 3.93 (s, 5H) , 3.40 (dd, J ＝ 13.5, 6.7 Hz, 1H) , 2.82 –2.61 (m, 2H) , 2.56 (s, 3H) , 2.41 (s, 1H) , 2.39 –2.20 (m, 4H) , 2.01 (dd, J ＝ 23.5, 11.7 Hz, 2H) , 1.80 –1.64 (m, 3H) , 1.56 (dd, J ＝ 9.0, 5.7 Hz, 1H) , 1.41 (dd, J ＝ 21.4, 15.2 Hz, 12H) , 1.27 (s, 2H) , 0.80 (d, J ＝ 12.1 Hz, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 19.

Example 20 Preparation and identification of benzene sulfonate amorphism of compound (I)

1. Preparation of benzene sulfonate amorphism of compound (I)

Compound (I) (633 mg, 0.716mmol) was dispersed in a mixture of methanol (12.0 mL) and dichloromethane (1.0 mL) , to the solution was added a benzene sulfonic acid (118 mg, 0.709 mmol) /methanol (4.5 mL) solution. The resulting solution was stirred at rt for 4 hours, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get benzene sulfonate amorphism of compound (I) (710 mg, 0.69 mmol, 96.4％) as a yellow solid.

2. Identification of benzene sulfonate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.38 (s, 1H) , 8.38 (s, 1H) , 8.27 (s, 1H) , 8.11 (d, J ＝ 9.0 Hz, 1H) , 7.98 (s, 1H) , 7.89 (s, 2H) , 7.47 (d, J ＝ 7.0 Hz, 1H) , 7.37 (d, J ＝ 13.1 Hz, 3H) , 7.23 (d, J ＝ 9.1 Hz, 1H) , 6.47 (s, 1H) , 5.85 (s, 1H) , 5.64 (dd, J ＝ 17.9, 8.2 Hz, 1H) , 5.04 (t, J ＝ 9.5 Hz, 1H) , 4.89 (d, J ＝ 7.0 Hz, 1H) , 4.64 (s, 1H) , 4.39 (d, J ＝ 11.6 Hz, 1H) , 4.17 (d, J ＝ 10.3 Hz, 2H) , 3.94 (s, 4H) , 3.52 –3.32 (m, 2H) , 2.71 (d, J ＝ 29.9 Hz, 2H) , 2.56 (s, 3H) , 2.47 –2.25 (m, 2H) , 1.97 (s, 2H) , 1.83 –1.62 (m, 3H) , 1.56 (s, 1H) , 1.47 –1.36 (m, 11H) , 1.27 (d, J ＝ 6.9 Hz, 2H) , 0.78 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 20.

Example 21 Preparation and identification of mesylate amorphism of compound (I)

1. Preparation of mesylate amorphism of compound (I)

Compound (I) (644 mg, 0.729 mmol) was dissolved in tetrahydrofuran (13.0 mL) , to the solution was added a methanesulfonic acid (74.3 mg, 0.765 mmol) /tetrahydrofuran (2.0 mL) solution. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo and methanol (19.0 mL) was added. The mixture was stirred and the solid was dissolved, the solvent was removed in vacuo again. The residue was dried at 60 ℃ in vacuo overnight to get mesylate amorphism of compound (I) (680 mg, 0.70 mmol, 96.0％) as a yellow solid.

2. Identification of mesylate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.34 (s, 1H) , 8.42 (d, J ＝ 1.6 Hz, 1H) , 8.07 (d, J ＝ 9.2 Hz, 1H) , 7.99 (s, 1H) , 7.89 (s, 1H) , 7.54 (d, J ＝ 7.5 Hz, 1H) , 7.33 (s, 1H) , 7.26 (s, 1H) , 6.57 (d, J ＝ 1.5 Hz, 1H) , 5.86 (s, 1H) , 5.68 (dd, J ＝ 18.3, 8.5 Hz, 1H) , 5.10 (t, J ＝ 9.6 Hz, 1H) , 4.85 –4.59 (m, 2H) , 4.46 –4.31 (m, 2H) , 3.96 (s, 3H) , 3.71 (s, 3H) , 3.47 (dt, J ＝ 13.6, 6.8 Hz, 2H) , 2.87 – 2.76 (m, 5H) , 2.64 –2.55 (m, 3H) , 2.50 –2.38 (m, 1H) , 2.30 (d, J ＝ 8.8 Hz, 1H) , 2.09 –1.95 (m, 2H) , 1.89 –1.69 (m, 3H) , 1.64 –1.51 (m, 5H) , 1.47 (d, J ＝ 6.9 Hz, 6H) , 1.27 (s, 2H) , 0.82 (t, J ＝5.8 Hz, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 21.

Example 22 Preparation and identification of sulfate amorphism of compound (I)

1. Preparation of sulfate amorphism of compound (I)

Compound (I) (718 mg, 0.803mmol) was dissolved in tetrahydrofuran (14.0 mL) , to the solution was added a sulfuric acid (80.1 mg, 0.803 mmol) /tetrahydrofuran (1.0 mL) solution slowly. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get sulfate amorphism of compound (I) (730 mg, 0.75 mmol, 93.4％) as a yellow solid.

2. Identification of sulfate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.55 (s, 1H) , 8.41 (d, J ＝ 1.5 Hz, 1H) , 8.15 (d, J ＝ 9.3 Hz, 1H) , 7.92 (d, J ＝ 10.7 Hz, 2H) , 7.57 (d, J ＝ 7.6 Hz, 1H) , 7.45 (s, 1H) , 7.35 (d, J ＝ 9.4 Hz, 1H) , 6.58 (s, 1H) , 5.88 (s, 1H) , 5.66 (dd, J ＝ 18.5, 8.6 Hz, 1H) , 5.11 (t, J ＝ 9.6 Hz, 1H) , 4.88 (t, J ＝ 8.0 Hz, 1H) , 4.79 (t, J ＝ 7.1 Hz, 1H) , 4.52 (d, J ＝ 9.7 Hz, 1H) , 4.36 (d, J ＝ 11.4 Hz, 1H) , 3.99 (s, 3H) , 3.47 (dd, J ＝ 13.8, 6.9 Hz, 1H) , 2.86 (dd, J ＝ 17.2, 8.7 Hz, 2H) , 2.57 (s, 3H) , 2.44 –2.18 (m, 2H) , 2.15 –1.96 (m, 2H) , 1.91 –1.78 (m, 2H) , 1.73 –1.60 (m, 2H) , 1.46 (dd, J ＝ 7.8, 4.5 Hz, 12H) , 1.38 –1.26 (m, 3H) , 0.89 (d, J ＝ 7.0 Hz, 1H) , 0.78 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 22.

Example 23 Preparation and identification of phosphate amorphism of compound (I)

1. Preparation of phosphate amorphism of compound (I)

Compound (I) (967 mg, 1.095 mmol) was dissolved in tetrahydrofuran (20.0 mL) , to the solution was added a phosphoric acid (126 mg, 1.093 mmol) /tetrahydrofuran (2.0 mL) solution slowly. The resulting solution was stirred at rt for 4 hours, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get phosphate amorphism of compound (I) (980 mg, 1.0 mmol, 91.3％) as a yellow solid.

2. Identification of phosphate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.18 (s, 1H) , 8.43 (d, J ＝ 1.5 Hz, 1H) , 7.90 (d, J ＝ 9.1 Hz, 1H) , 7.70 (d, J ＝ 7.6 Hz, 1H) , 7.57 (s, 1H) , 7.32 (s, 1H) , 7.10 (d, J ＝ 9.2 Hz, 1H) , 7.05 (s, 1H) , 6.61 (d, J ＝ 1.4 Hz, 1H) , 5.80 –5.65 (m, 1H) , 5.58 (s, 1H) , 5.05 –4.96 (m, 1H) , 4.80 (t, J ＝7.4 Hz, 1H) , 4.69 (t, J ＝ 7.9 Hz, 1H) , 4.58 (d, J ＝ 11.4 Hz, 1H) , 4.16 (dd, J ＝ 11.2, 3.5 Hz, 1H) , 4.02 –3.82 (m, 4H) , 3.78 –3.63 (m, 1H) , 3.23 (dt, J ＝ 13.6, 6.8 Hz, 1H) , 2.83 –2.64 (m, 5H) , 2.52 (dd, J ＝ 17.0, 8.5 Hz, 1H) , 2.39 –2.21 (m, 1H) , 2.12 –1.99 (m, 2H) , 1.91 –1.85 (m, 3H) , 1.82 –1.65 (m, 3H) , 1.51 (s, 4H) , 1.41 (d, J ＝ 6.9 Hz, 6H) , 1.29 (dd, J ＝ 19.5, 7.4 Hz, 2H) , 0.91 –0.77 (m, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 23.

Example 24 Preparation and identification of nitrate amorphism of compound (I)

1. Preparation of nitrate amorphism of compound (I)

Compound (I) (672 mg, 0.755 mmol) was dissolved in tetrahydrofuran (14.0 mL) , to the solution was added a nitric acid (73.5 mg, 0.758 mmol) /tetrahydrofuran (2.0 mL) solution slowly. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get nitrate amorphism of compound (I) (650 mg, 0.69 mmol, 91.4％) as a yellow solid.

2. Identification of nitrate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H) , 8.42 (d, J ＝ 1.5 Hz, 1H) , 8.09 (d, J ＝ 9.2 Hz, 1H) , 7.97 (s, 1H) , 7.77 (s, 1H) , 7.50 (d, J ＝ 7.3 Hz, 1H) , 7.36 (s, 1H) , 7.29 (d, J ＝ 4.9 Hz, 1H) , 6.53 (d, J ＝ 1.5 Hz, 1H) , 5.80 –5.61 (m, 2H) , 5.13 –5.02 (m, 1H) , 4.83 (t, J ＝ 7.9 Hz, 1H) , 4.73 (t, J ＝ 6.9 Hz, 1H) , 4.53 (d, J ＝ 11.8 Hz, 1H) , 4.25 (dd, J ＝ 11.7, 3.6 Hz, 1H) , 3.97 (s, 3H) , 3.38 (dd, J ＝ 13.7, 6.9 Hz, 1H) , 2.77 (d, J ＝ 7.6 Hz, 2H) , 2.60 (s, 3H) , 2.46 (d, J ＝ 9.1 Hz, 1H) , 2.32 (dd, J ＝ 17.5, 8.8 Hz, 1H) , 2.00 (dd, J ＝ 15.9, 6.9 Hz, 2H) , 1.79 (ddd, J ＝ 32.8, 14.6, 8.8 Hz, 3H) , 1.59 (dd, J ＝ 8.8, 5.2 Hz, 1H) , 1.54 –1.39 (m, 13H) , 1.28 (dd, J ＝ 20.6, 10.6 Hz, 3H) , 0.90 –0.76 (m, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 24.

Example 25 Preparation and identification of 1, 5-naphthalenedisulfonate amorphism of compound (I)

1. Preparation of 1, 5-naphthalenedisulfonate amorphism of compound (I)

Compound (I) (665 mg, 0.747mmol) was dispersed in methanol (14.0 mL) , to the solution was added a 1, 5-naphthalenedisulfonic acid (216.8 mg, 0.745 mmol) /methanol (2.0 mL) solution. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get 1, 5-naphthalenedisulfonate amorphism of compound (I) (780 mg, 0.67 mmol, 89.7％) as a yellow solid.

2. Identification of 1, 5-naphthalenedisulfonate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.59 (s, 1H) , 8.54 (s, 1H) , 8.47 (s, 1H) , 8.39 (d, J ＝ 8.0 Hz, 1H) , 7.88 (d, J ＝ 9.3 Hz, 1H) , 7.70 (d, J ＝ 6.9 Hz, 1H) , 7.48 (d, J ＝ 7.8 Hz, 1H) , 7.34 (s, 1H) , 7.17 (s, 1H) , 7.10 (d, J ＝ 9.5 Hz, 1H) , 6.70 (d, J ＝ 7.1 Hz, 1H) , 6.55 (s, 1H) , 5.76 –5.61 (m, 1H) , 5.47 (s, 1H) , 5.17 –5.03 (m, 1H) , 4.90 (d, J ＝ 7.7 Hz, 1H) , 4.70 (s, 1H) , 4.44 (d, J ＝ 11.6 Hz, 1H) , 4.12 –3.93 (m, 3H) , 3.74 (dd, J ＝ 14.0, 6.9 Hz, 1H) , 3.26 (dd, J ＝ 13.5, 6.8 Hz, 1H) , 2.57 (s, 3H) , 2.44 (d, J ＝ 8.7 Hz, 2H) , 2.15 (s, 7H) , 1.85 –1.60 (m, 4H) , 1.59 –1.23 (m, 16H) , 0.84 (d, J ＝ 5.9 Hz, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 25.

Example 26 Preparation and identification of 1, 2-ethanedisulphonate amorphism of compound (I)

1. Preparation of 1, 2-ethanedisulphonate amorphism of compound (I)

Compound (I) (695 mg, 0.781 mmol) was dispersed in methanol (14.0 mL) , to the solution was added a 1, 2-ethanedisulfonic acid (153.1 mg, 0.781 mmol) /methanol (2.0 mL) solution. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get 1, 2-ethanedisulfonate amorphism of compound (I) (810 mg, 0.76 mmol, 97.3％) as a yellow solid.

2. Identification of 1, 2-ethanedisulfonate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.33 (s, 1H) , 8.43 (t, J ＝ 7.3 Hz, 1H) , 8.12 –7.98 (m, 1H) , 7.69 (d, J ＝ 7.4 Hz, 1H) , 7.60 (d, J ＝ 7.3 Hz, 1H) , 7.25 (s, 1H) , 7.22 (d, J ＝ 4.4 Hz, 1H) , 6.69 (s, 1H) , 6.61 (s, 1H) , 5.69 (dd, J ＝ 18.6, 7.8 Hz, 2H) , 5.33 (dd, J ＝ 48.2, 38.5 Hz, 1H) , 5.10 –4.96 (m, 1H) , 4.84 (ddd, J ＝ 25.3, 15.9, 7.1 Hz, 2H) , 4.55 (d, J ＝ 11.4 Hz, 1H) , 4.25 (t, J ＝ 19.1 Hz, 1H) , 3.98 (d, J ＝ 10.2 Hz, 3H) , 3.49 (s, 1H) , 3.30 (d, J ＝ 6.8 Hz, 3H) , 2.79 (dd, J ＝ 27.7, 8.3 Hz, 2H) , 2.63 (d, J ＝ 5.7 Hz, 4H) , 2.37 –2.17 (m, 2H) , 2.16 –1.85 (m, 3H) , 1.85 –1.64 (m, 3H) , 1.61 –1.55 (m, 2H) , 1.50 (s, 3H) , 1.43 (t, J ＝ 6.6 Hz, 8H) , 1.28 (s, 2H) , 0.83 (dd, J ＝ 8.0, 6.6 Hz, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 26.

Example 27 Preparation and identification of β-naphthalenesulfonate amorphism of compound (I)

1. Preparation of β-naphthalenesulfonate amorphism of compound (I)

Compound (I) (693 mg, 0.775 mmol) was suspended in methanol (14.0 mL) , to the solution was added a β-naphthalenesulfonic acid (179.6 mg, 0.78 mmol) /methanol (2.0 mL) solution, and dichloromethane (6.0 mL) was added. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get β-naphthalenesulfonate amorphism of compound (I) (790 mg, 0.73 mmol, 94.2％) as a yellow solid.

2. Identification of β-naphthalenesulfonate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.43 (s, 1H) , 8.37 (d, J ＝ 10.5 Hz, 2H) , 8.27 (s, 1H) , 8.09 (d, J ＝ 9.2 Hz, 1H) , 7.92 (d, J ＝ 8.4 Hz, 2H) , 7.82 (d, J ＝ 7.8 Hz, 1H) , 7.76 (t, J ＝ 7.0 Hz, 2H) , 7.47 (dd, J ＝ 18.4, 7.1 Hz, 3H) , 7.33 (s, 1H) , 7.11 (d, J ＝ 9.4 Hz, 1H) , 6.46 (s, 1H) , 5.90 (s, 1H) , 5.63 (dd, J ＝ 18.1, 8.3 Hz, 1H) , 5.06 (t, J ＝ 9.6 Hz, 1H) , 4.95 (t, J ＝ 7.9 Hz, 1H) , 4.64 (s, 1H) , 4.39 (d, J ＝ 11.7 Hz, 1H) , 4.18 (d, J ＝ 9.1 Hz, 1H) , 3.86 (s, 3H) , 3.42 –3.23 (m, 5H) , 2.90 –2.61 (m, 2H) , 2.52 (s, 3H) , 2.45 –2.22 (m, 2H) , 1.96 (s, 2H) , 1.79 –1.64 (m, 3H) , 1.58 (dd, J ＝9.2, 5.7 Hz, 1H) , 1.48 (s, 3H) , 1.38 –1.33 (m, 7H) , 1.28 (s, 2H) , 0.84 –0.72 (m, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 27.

Example 28 Preparation and identification of cyclamate amorphism of compound (I)

1. Preparation of cyclamate amorphism of compound (I)

Compound (I) (730 mg, 0.816 mmol) was dispersed in methanol (22.0 mL) , to the solution was added a cyclamic acid (149.3 mg, 0.816 mmol) /methanol (2.0 mL) solution. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get cyclamate amorphism of compound (I) (820 mg, 0.78 mmol, 95.6％) as a yellow solid.

2. Identification of cyclamate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.22 (s, 1H) , 8.44 (d, J ＝ 1.6 Hz, 1H) , 7.97 (d, J ＝ 9.1 Hz, 1H) , 7.63 (d, J ＝ 7.5 Hz, 1H) , 7.58 (s, 1H) , 7.51 (s, 1H) , 7.16 (s, 2H) , 6.62 (d, J ＝ 1.6 Hz, 1H) , 5.72 (dd, J ＝ 18.3, 8.5 Hz, 1H) , 5.62 (s, 1H) , 5.06 (t, J ＝ 9.5 Hz, 1H) , 4.91 –4.65 (m, 2H) , 4.54 (d, J ＝ 11.6 Hz, 1H) , 4.21 (dd, J ＝ 11.3, 3.3 Hz, 1H) , 3.93 (s, 3H) , 3.44 (d, J ＝ 11.0 Hz, 1H) , 3.25 (dt, J ＝ 20.7, 6.9 Hz, 2H) , 2.78 (p, J ＝ 14.2 Hz, 3H) , 2.65 (s, 3H) , 2.52 (d, J ＝ 9.2 Hz, 1H) , 2.37 –2.16 (m, 3H) , 1.94 (ddd, J ＝ 26.6, 14.0, 9.0 Hz, 4H) , 1.76 (t, J ＝ 11.6 Hz, 4H) , 1.65 –1.54 (m, 3H) , 1.52 (s, 4H) , 1.48 (d, J ＝ 6.5 Hz, 3H) , 1.42 (d, J ＝ 6.9 Hz, 6H) , 1.30 (d, J ＝ 16.3 Hz, 4H) , 1.23 –1.13 (m, 1H) , 0.86 –0.76 (m, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 28.

Example 29 Preparation and identification of isethionate amorphism of compound (I)

1. Preparation of isethionate amorphism of compound (I)

Compound (I) (651 mg, 0.732 mmol) was dispersed in methanol (14.0 mL) , to the solution was added an isethionic acid (115.9 mg, 0.735 mmol) /methanol (2.0 mL) solution, and dichloromethane (2.0 mL) was added. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get isethionate amorphism of compound (I) (710 mg, 0.71 mmol, 97.0％) as a yellow solid.

2. Identification of isethionate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H) , 8.43 (d, J ＝ 1.2 Hz, 1H) , 8.24 –8.04 (m, 2H) , 7.82 (s, 1H) , 7.49 (d, J ＝ 7.3 Hz, 1H) , 7.39 (s, 1H) , 7.31 (d, J ＝ 9.5 Hz, 1H) , 6.54 (d, J ＝ 1.2 Hz, 1H) , 5.90 (s, 1H) , 5.67 (dd, J ＝ 17.9, 8.4 Hz, 1H) , 5.06 (t, J ＝ 9.6 Hz, 1H) , 4.87 (t, J ＝ 8.0 Hz, 1H) , 4.71 (t, J ＝ 6.9 Hz, 1H) , 4.49 (d, J ＝ 11.6 Hz, 1H) , 4.30 (d, J ＝ 8.5 Hz, 1H) , 3.99 (d, J ＝10.1 Hz, 5H) , 3.43 (dt, J ＝ 13.5, 6.7 Hz, 1H) , 3.16 –3.04 (m, 2H) , 2.82 (dd, J ＝ 19.8, 11.8 Hz, 2H) , 2.59 (s, 3H) , 2.45 (s, 1H) , 2.32 (dd, J ＝ 17.4, 8.7 Hz, 1H) , 2.00 (dd, J ＝ 23.7, 10.9 Hz, 2H) , 1.85 –1.67 (m, 3H) , 1.61 (dd, J ＝ 9.4, 5.8 Hz, 1H) , 1.55 –1.39 (m, 13H) , 1.29 (d, J ＝ 15.1 Hz, 3H) , 0.81 (s, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 29.

Example 30 Preparation and identification of maleate amorphism of compound (I)

1. Preparation of maleate amorphism of compound (I)

Compound (I) (622 mg, 0.699 mmol) was dissolved in acetone (12.0 mL) , to the solution was added a maleic acid (81.5 mg, 0.699 mmol) /acetone (3.0 mL) solution slowly. The resulting solution was stirred at rt overnight, and the solvent was removed in vacuo. The residue was dried at 60 ℃ in vacuo overnight to get maleate amorphism of compound (I) (650 mg, 0.66 mmol, 94.4％) as a yellow solid.

2. Identification of maleate amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.23 (s, 1H) , 8.45 (d, J ＝ 1.3 Hz, 1H) , 8.01 (d, J ＝ 9.2 Hz, 1H) , 7.68 –7.49 (m, 3H) , 7.19 (t, J ＝ 4.6 Hz, 2H) , 6.61 (d, J ＝ 1.3 Hz, 1H) , 6.33 (s, 2H) , 5.78 –5.57 (m, 2H) , 5.11 –4.95 (m, 1H) , 4.76 (t, J ＝ 7.5 Hz, 2H) , 4.61 (d, J ＝ 11.7 Hz, 1H) , 4.16 (s, 1H) , 3.96 (s, 3H) , 3.27 (dt, J ＝ 13.7, 6.9 Hz, 1H) , 2.84 –2.69 (m, 2H) , 2.65 (s, 3H) , 2.53 (s, 1H) , 2.32 (dd, J ＝ 17.3, 8.6 Hz, 1H) , 2.14 –1.83 (m, 3H) , 1.82 –1.68 (m, 2H) , 1.62 –1.22 (m, 18H) , 0.92 –0.77 (m, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 30.

Example 31 Preparation and identification of hydrobromide amorphism of compound (I)

1. Preparation of hydrobromide amorphism of compound (I)

Compound (I) (697 mg, 0.789 mmol) was dissolved in tetrahydrofuran (14.0 mL) , to the solution was added hydrobromic acid (146.3 mg, 0.868 mmol) dropwise. The resulting solution was stirred at rt overnight, and the mixture was filtered by suction. The filter cake was washed with tetrahydrofuran (0.5 mL×2) and sucked to dry, and then dried at 60 ℃ in vacuo overnight to get hydrobromide amorphism of compound (I) (520 mg, 0.54 mmol, 68.4％) as a yellow solid.

2. Identification of hydrobromide amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.20 (s, 1H) , 8.42 (d, J ＝ 1.4 Hz, 2H) , 8.04 (d, J ＝ 8.9 Hz, 1H) , 7.54 (s, 1H) , 7.43 (d, J ＝ 7.1 Hz, 1H) , 7.36 (s, 1H) , 7.28 –7.22 (m, 1H) , 6.54 (s, 1H) , 5.93 (s, 1H) , 5.73 (dd, J ＝ 18.5, 9.0 Hz, 1H) , 5.18 –4.94 (m, 1H) , 4.78 (s, 1H) , 4.44 (s, 1H) , 3.99 (s, 3H) , 3.62 (s, 1H) , 2.88 (s, 1H) , 2.79 (d, J ＝ 6.8 Hz, 1H) , 2.65 (s, 3H) , 2.49 (s, 1H) , 2.30 (dd, J ＝ 16.7, 7.9 Hz, 1H) , 2.02 –1.75 (m, 10H) , 1.60 –1.47 (m, 10H) , 1.29 (d, J ＝ 11.2 Hz, 4H) , 0.85 (d, J ＝ 10.9 Hz, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 31.

Example 32 Preparation and identification of hydrochloride amorphism of compound (I)

1. Preparation of hydrochloride amorphism of compound (I)

Compound (I) (685 mg, 0.766 mmol) was dispersed in methanol (14.0 mL) , and to the solution was added a hydrogen chloride solution in ethyl acetate (1.91 mmol, 0.1 mL) . The resulting solution was stirred at rt for 4 hours, and dichloromethane (1.0 mL) was added. The solvent was removed in vacuo. The residue was dried at rt in vacuo overnight to get hydrochloride amorphism of compound (I) (655mg, 0.719 mmol, 93.9％) as a yellow solid.

2. Identification of hydrochloride salt amorphism of compound (I)

1) ¹H NMR (400 MHz, CDCl₃) δ 10.17 (s, 1H) , 8.44 (s, 1H) , 7.93 (d, J ＝ 9.2 Hz, 1H) , 7.71 (s, 1H) , 7.55 (d, J ＝ 7.0 Hz, 1H) , 7.18 –7.06 (m, 3H) , 6.63 (s, 1H) , 5.74 (dd, J ＝ 18.0, 8.5 Hz, 1H) , 5.62 (s, 1H) , 5.04 (t, J ＝ 9.4 Hz, 1H) , 4.80 (t, J ＝ 7.4 Hz, 1H) , 4.69 (t, J ＝ 7.8 Hz, 1H) , 4.54 (d, J ＝ 11.5 Hz, 1H) , 4.23 (s, 1H) , 3.95 (s, 3H) , 3.28 (s, 1H) , 2.77 (d, J ＝ 5.2 Hz, 2H) , 2.69 (s, 3H) , 2.54 (s, 1H) , 2.47 (dd, J ＝ 14.7, 7.3 Hz, 1H) , 2.31 (dd, J ＝ 17.5, 8.7 Hz, 1H) , 2.16 (s, 1H) , 2.05 (dd, J ＝ 23.1, 12.2 Hz, 1H) , 1.99 –1.88 (m, 2H) , 1.79 (d, J ＝ 10.8 Hz, 2H) , 1.53 (d, J ＝ 7.9 Hz, 6H) , 1.43 (d, J ＝ 6.8 Hz, 6H) , 1.35 –1.26 (m, 2H) , 1.08 (t, J ＝ 7.3 Hz, 1H) , 0.88 –0.79 (m, 2H) ppm.

2) The XRPD pattern was analyzed and identified by using Empyrean X-ray powder diffraction (XRPD) and Cu-Kα radiation, the result was as shown in Figure 32.

Example 33: PK test of the salts of compound (I) of the invention in male SD rats

Test method

Male SD rats (190-250 g) were grouped according to 3 animals per each salt type group, which were administered respectively with test compound at a dosage of 100 mg/kg by oral. Blood samples were collected at 0.25, 0.5, 1, 2, 5, 7 and 24 hours after the administration. Standard curve was plotted based on concentrations of the samples in a suitable range, and the concentrations of test compounds in plasma samples were determined in MRM mode by using AB SCIEX API4000 LC-MS/MS. Pharmacokinetic parameters were calculated according to drug concentration -time curve using a noncompartmental method by WinNonLin 6.3 software.

The results were shown as table 2.

Table 2: PK data of salts of compound (I) in SD rats

The results in table 2 show that the exposure of the salts of compound (I) provided herein is better than amorphism of compound (I) after administering orally to SD rats, especially sodium salt amorphism of compound (I) , L-arginine salt amorphism of compound (I) and nitrate amorphism of compound (I) have a significant advantage, the exposure of which are respectively14110 h*ng/ml, 15000 h*ng/ml and 16100 h*ng/ml, which indicates that salts of compound (I) can be absorbed well in vivo.

Though the invention is described in detail in the above with reference to general description and detailed embodiments, modifications and variants are possible obvious to a person of ordinary skills in the art may be made based on the invention. Therefore, the modifications and variants all belong to the scopes of the invention without departing from the spirits of the invention.

Claims

A pharmaceutically acceptable base addition salt of compound (I) ,
The base addition salt of claim 1, wherein the salt is selected from at least one of lithium salt, sodium salt, potassium salt, calcium salt, magnesium salt, aluminium salt, ferric salt, zinc salt, ammonium salt； or the salt is selected from at least one of salts formed by compound (I) and methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tromethamine, diethylaminoethanol, isopropylamine, 2-ethylaminoethanol, pyridine, methyl pyridine, ethanolamine, diethanolamine, ammonium, dimethylethanolamine, tetramethylammonium, tetraethylammonium, triethanolamine, piperidine, piperazine, morpholine, imidazole, L-arginine, histidine, N-methylglucosamine, dimethylglucosamine, ethylglucosamine, dicyclohexyl amine, 1, 6-hexanediamine, ethylenediamine, glucosamine, sarcosine, serinol, amino propanediol, 1-amino-2, 3, 4-butanetriol, L-lysine, ornithine.
A pharmaceutically acceptable acid addition salt of compound (I) ,
The acid addition salt of claim 3, wherein the salt is an inorganic acid salt or organic acid salt； wherein the inorganic acid salt is selected from at least one of hydrochloride, sulfate, hydrosulfate, nitrate, hydrobromide, hydriodate, carbonate, bicarbonate, sulfite, bisulfite, pyrosulfate, monohydric phosphate, dihydric phosphate, perchlorate, persulfate, hemisulphate, bisulphate, thiocyanate, phosphate, pyrophosphate and metaphosphate； the organic acid salt is selected from at least one of formate, acetate, propionate, butyrate, benzoate, malonate, succinate, pyruvate, mesylate, ethanesulfonate, propanesulfonate, citrate, 4-nitrobenzoate, benzene sulfonate, tosilate, 1, 2-ethanedisulphonate, β-naphthalenesulfonate, malate, propiolate, 2-butynoate, 2-hydroxy-ethanesulfonate, vinyl acetate, tartrate, fumarate, hydroxy ethylene sulfonate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, gluceptate, mandelate, 1, 2-ethanedisulfonate, oxalate, trifluoroacetate, trifluoromethanesulfonate, adipate, suberate, sebacate, butyne-1, 4-dioate, hexene-1, 6-dioate, hydroxyacetate, alginate, ascorbate, aspartate, glutamate, 2-phenoxybenzoate, 2- (4-hydroxybenzoyl) benzoate, acetoacetate, 2-hydroxyethanesulfonate, borate, chlorobenzoate, camphorate, itaconate, camphorsulfonate, methylbenzoate, dinitrobenzoate, sulfamate, galacturonate, cyclopentylpropanoate, dodecyl sulfate, acrylate, cypionate, glycerophosphate, methoxybenzoate, digluconate, gluconate, heptylate, hexanoate, pivalate, glucuronate, laurate, phthalate, phenylacetate, laurylsulfate, 2-acetoxybenzoate, nicotinate, cinnamate, oleate, palmitate, pectate, benzenedicarboxylate, glutarate, hydroxymaleate, hydroxybenzoate, phenylacetate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, isobutyrate, pivalate, picrate, stearate, 2, 2-dichloroacetate, acylated amino-acid salt, alginate, 4-acetamidobenzene sulfonate, decanoate, cholate, caprylate, pelargonate, cyclamate, phthalate, hydrochloride cysteine salt, sorbate, hydrochloride glycinate, 1, 5-naphthalenedisulfonate, xylene sulfonate, dihydrochloride cystine salt, undecanoate, poly (vinylsulfonate) , sulfosalicylate, phenylbutyrate, 4-hydroxybutyrate, poly (vinylsulfate) , naphthalene-1-sulfonate and valerate.
A pharmaceutical composition comprising the base addition salt of any one of claims 1 to 2 or the acid addition salt of any one of claims 3 to 4, optionally the pharmaceutical composition further comprises a pharmaceutically acceptable adjuvant.
The pharmaceutical composition of claim 5 further comprising one or more other anti-HCV agents, wherein the other anti-HCV agent is interferon, ribavirin, IL-2, IL-6, IL-12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA for silencing or down-regulating positive-strand RNA genome of HCV, anti-sense RNA for silencing or down-regulating positive-strand RNA genome of HCV, imiquimod, an inosine 5’ -monophosphate dehydrogenase inhibitor, amantadine, rimantadine, ritonavir, bavituximab, Civacir^TM, boceprevir, telaprevir, sofosbuvir, ledipasvir, daclatasvir, danoprevir, ciluprevir, narlaprevir, deleobuvir, dasabuvir, beclabuvir, elbasvir, ombitasvir, neceprevir, tegobuvir, grazoprevir, sovaprevir, samatasvir, veruprevir, erlotinib, simeprevir, asunaprevir, vaniprevir, faldaprevir, VX-135, CIGB-230, furaprevir, pibrentasvir, glecaprevir, uprifosbuvir, radalbuvir, JHJ-56914845, vedroprevir, BZF-961, GS-9256, ANA975, EDP239, ravidasvir hydrochloride, velpatasvir, MK-8325, GSK-2336805, PPI-461, ACH-1095, VX-985, IDX-375, VX-500, VX-813, PHX-1766, PHX-2054, IDX-136, IDX-316, modithromycin, VBY-376, TMC-649128, mericitabine, INX-189, IDX-184, IDX102, R1479, UNX-08189, PSI-6130, PSI-938, PSI-879, HCV-796, nesbuvir, VCH-916, lomibuvir, setrobuvir, MK-3281, ABT-072, filibuvir, A-837093, JKT-109, Gl-59728, GL-60667, AZD-2795, TMC-647055 or a combination thereof； wherein the interferon is interferon α-2b, pegylated interferon α, interferon α-2a, pegylated interferon α-2a, consensus interferon-α, interferon γ or a combination thereof.
The pharmaceutical composition of claim 5 further comprising at least one HCV inhibitor, wherein the HCV inhibitor is used for inhibiting HCV replication process and/or HCV viral protein function, and wherein the HCV replication process is selected from at least one of HCV entry, uncoating, translation, replication, assembly and egress process； and wherein the HCV viral protein is selected from at least one of metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A, NS5B, and an internal ribosome entry site and inosine-5’ -monophosphate dehydrogenase required in HCV viral replication.
Use of the base addition salt of any one of claims 1 to 2 or the acid addition salt of any one of claims 3 to 4 or the pharmaceutical composition of any one of claims 5 to 7 in the manufacture of a medicament for inhibiting HCV replication process and/or HCV viral protein function, wherein the HCV replication process is selected from at least one of HCV entry, uncoating, translation, replication, assembly and egress process； and wherein the HCV viral protein is selected from at least one of metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A, NS5B, and an internal ribosome entry site and inosine-5’ -monophosphate dehydrogenase required in HCV viral replication.
Use of the base addition salt of any one of claims 1 to 2 or the acid addition salt of any one of claims 3 to 4 or the pharmaceutical composition of any one of claims 5 to 7 in the manufacture of a medicament for preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient.
The base addition salt of any one of claims 1 to 2 or the acid addition salt of any one of claims 3 to 4 or the pharmaceutical composition of any one of claims 5 to 7 for use in inhibiting HCV replication process and/or HCV viral protein function, wherein the HCV replication process is selected from at least one of HCV entry, uncoating, translation, replication, assembly and egress process； and wherein the HCV viral protein is selected from at least one of metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A, NS5B, and an internal ribosome entry site and inosine-5’ -monophosphate dehydrogenase required in HCV viral replication.
The base addition salt of any one of claims 1 to 2 or the acid addition salt of any one of claims 3 to 4 or the pharmaceutical composition of any one of claims 5 to 7 for use in preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient.
A method of inhibiting HCV replication process and/or HCV viral protein function, comprising administering the base addition salt of any one of claims 1 to 2 or the acid addition salt of any one of claims 3 to 4 or the pharmaceutical composition of any one of claims 5 to 7 to the patient, wherein the HCV replication process is selected from at least one of HCV entry, uncoating, translation, replication, assembly and egress process； and wherein the HCV viral protein is selected from at least one of metalloproteinase, non-structural protein NS2, NS3, NS4A, NS4B, NS5A or NS5B, an internal ribosome entry site and inosine-5’ -monophosphate dehydrogenase required in HCV viral replication.
A method of preventing, managing, treating or lessening the severity of HCV infection or a HCV disorder in a patient comprising administering the base addition salt of any one of claims 1 to 2 or the acid addition salt of any one of claims 3 to 4 or the pharmaceutical composition of any one of claims 5 to 7 to the patient.